| Andrews, B.T., Gosavi, S., Finke, J.M., Onuchic, J.N. & Jennings, P.A. (2008), "The dual-basin landscape of GFP folding", Proceedings Of The National Academy Of Sciences Of The United States Of America. , pp. (in press).
[BibTeX] [DOI]
|
BibTeX:
@article{Andrews,
author = {Andrews, B. T. and Gosavi, S. and Finke,J. M. and Onuchic, J. N. and Jennings, P. A.},
title = {The dual-basin landscape of GFP folding},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2008},
pages = {(in press)},
doi = {doi:10.1073/pnas.0804039105}
}
|
| Gosavi, S., Whitford, P.C., Jennings, P.A. & Onuchic, J.N. (2008), "Extracting function from a beta-trefoil folding motif", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 105(30), pp. 10384-10389.
[Abstract] [BibTeX]
|
| Abstract: Despite having remarkably similar three-dimensional structures and stabilities, IL-1 beta promotes signaling, whereas IL-1Ra inhibits it. Their energy landscapes are similar and have coevolved to facilitate competitive binding to the IL-1 receptor. Nevertheless, we find that IL-1Ra folds faster than IL-1 beta. A structural alignment of the proteins shows differences mainly in two loops, a beta-bulge of IL-1 beta and a loop in IL-1 Ra that interacts with residue K145 and connects beta-strands 11 and 12. Bioassays indicate that inserting the beta-bulge from IL-1 beta confers partial signaling capability onto a K145D mutant of IL-1Ra. Based on the alignment, mutational assays and our computational folding results, we hypothesize that functional regions are not central to the beta-trefoil motif and cause slow folding. The IL-1 beta beta-bulge facilitates activity and replacing it by the IL-1Ra beta-turn results in a hybrid protein that folds fasterthan IL-1 beta. Inserting the beta 11-beta 12 connecting-loop, which aids inhibition, into either IL-1 beta or the hybrid protein slows folding. Thus, regions that aid function (either through activity or inhibition) can be inferred from folding traps via structural differences. Mapping functional properties onto the numerous folds determined in structural genomics efforts is an area of intense interest. Our studies provide a systematic approach to mapping the functional genomics of a fold family. |
BibTeX:
@article{Gosavi2008,
author = {Gosavi, S. and Whitford, P. C. and Jennings, P. A. and Onuchic, J. N.},
title = {Extracting function from a beta-trefoil folding motif},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2008},
volume = {105},
number = {30},
pages = {10384--10389}
}
|
| Oliveira, L.C., Schug, A. & Onuchic, J.N. (2008), "Geometrical features of the protein folding mechanism are a robust property of the energy landscape: A detailed investigation of several reduced models", Journal Of Physical Chemistry B. Vol. 112(19), pp. 6131-6136.
[Abstract] [BibTeX]
|
| Abstract: The concept of a funneled energy landscape and the principle of minimal frustration are the theoretical foundation justifying the applicability of structure-based models. In simulations, a protein is commonly reduced to a C-alpha-bead representation. These simulations are sufficient to predict the geometrical features of the folding mechanism observed experimentally utilizing a concise formulation of the Hamiltonian with low computational costs. Toward a better understanding of the interplay between energetic and geometrical features in folding, the side chain is now explicitly included in the simulations. The simplest choice is the addition of C-beta-beads at the center-of-mass position of the side chains. While one varies the energetic parameters of the model, the geometric aspects of the folding mechanism remain robust for a broad range of parameters. Energetic properties like folding barriers and protein stability are sensitive to the details of simulations. This robustness to geometry and sensitivity to energetic properties provide flexibility in choosing different parameters to represent changes in sequences, environments, stability or folding rate effects. Therefore, minimal frustration and the funnel concept guarantee that the geometrical features are robust properties of the folding landscape, while mutations and/or changes in the environment easily influence energy-dependent properties like folding rates or stability. |
BibTeX:
@article{Oliveira2008,
author = {Oliveira, L. C. and Schug, A. and Onuchic, J. N.},
title = {Geometrical features of the protein folding mechanism are a robust property of the energy landscape: A detailed investigation of several reduced models},
journal = {Journal Of Physical Chemistry B},
year = {2008},
volume = {112},
number = {19},
pages = {6131--6136}
}
|
| Onuchic, J.N., Kobayashi, C. & Baldridge, K.K. (2008), "Quantum tunneling in biological reactions: The interplay between theory and experiments", Journal Of The Brazilian Chemical Society. Vol. 19(2), pp. 206-210.
[Abstract] [BibTeX]
|
| Abstract: Ricardo Ferreira was the first Brazilian scientist to understand the need of solid theoretical approaches to obtain quantitative understanding mechanisms governing the life sciences. Therefore, in this issue in his honor, we decided to describe how theory has been able to guide the understanding of electron tunneling in biology. During almost twenth years, our Pathway model has been the most powerful model in terms of predicting the tunneling mechanism for electron transfer in biological systems, particularly proteins. Recently, we have generalized the conventional Pathway models to understand how protein dynamics modulate not only the Franck-Condon Factor but also the tunneling matrix element. The interference among pathways modulates the electron tunneling interactions in proteins ( particularly destructive interference), and dynamical effects are of critical importance. Tunneling can be controlled by protein conformations from equilibrium, which may be needed to minimize the effect of destructive interference during tunneling. In contrast, when equilibrium configurations have small destructive interference, electron tunneling is mediated by one ( or a few) constructively interfering pathway tubes and dynamical effects are modest. This new mechanism has predicted several experimental rates that were later confirmed by experiments. |
BibTeX:
@article{Onuchic2008,
author = {Onuchic, J. N. and Kobayashi, C. and Baldridge, K. K.},
title = {Quantum tunneling in biological reactions: The interplay between theory and experiments},
journal = {Journal Of The Brazilian Chemical Society},
year = {2008},
volume = {19},
number = {2},
pages = {206--210}
}
|
| Suzuki, Y., Noel, J.K. & Onuchic, J.N. (2008), "An analytical study of the interplay between geometrical and energetic effects in protein folding.", J Chem Phys. Vol. 128(2), pp. 025101.
[Abstract] [BibTeX]
|
| Abstract: Analytical studies have several advantages for an understanding of the mechanisms of protein folding such as the interplay between geometrical and energetic effects. In this paper, we introduce a Gaussian filament with a C(alpha) structure-based (Go) potential as a new theoretical scheme based on a Hamiltonian approach. This model takes into account geometrical information in a realistic fashion without the need of phenomenological descriptions. In order to make this model more appropriate for comparison with protein folding simulations and experiments, we introduce a many-body interaction into the potential term to enhance cooperativity. We apply our new analytical model to a beta-hairpin-type peptide and compare our results with a molecular dynamics simulation of a structure-based model. |
BibTeX:
@article{Suzuki2008a,
author = {Suzuki, Yoko and Noel, Jeff K. and Onuchic, Jose N.},
title = {An analytical study of the interplay between geometrical and energetic effects in protein folding.},
journal = {J Chem Phys},
year = {2008},
volume = {128},
number = {2},
pages = {025101}
}
|
| Suzuki, Y., Noel, J.K. & Onuchic, J.N. (2008), "An analytical study of the interplay between geometrical and energetic effects in protein folding", Journal Of Chemical Physics. Vol. 128
[Abstract] [BibTeX]
|
| Abstract: Analytical studies have several advantages for an understanding of the mechanisms of protein folding such as the interplay between geometrical and energetic effects. In this paper, we introduce a Gaussian filament with a C-alpha structure-based (G (o) over bar) potential as a new theoretical scheme based on a Hamiltonian approach. This model takes into account geometrical information in a realistic fashion without the need of phenomenological descriptions. In order to make this model more appropriate for comparison with protein folding simulations and experiments, we introduce a many-body interaction into the potential term to enhance cooperativity. We apply our new analytical model to a beta-hairpin-type peptide and compare our results with a molecular dynamics simulation of a structure-based model. (c) 2008 American Institute of Physics. |
BibTeX:
@article{Suzuki2008,
author = {Suzuki, Y. and Noel, J. K. and Onuchic, J. N.},
title = {An analytical study of the interplay between geometrical and energetic effects in protein folding},
journal = {Journal Of Chemical Physics},
year = {2008},
volume = {128}
}
|
| Whitford, P.C., Gosavi, S. & Onuchic, J.N. (2008), "Conformational transitions in adenylate kinase - Allosteric communication reduces misligation", Journal Of Biological Chemistry. Vol. 283, pp. 2042-2048.
[Abstract] [BibTeX]
|
| Abstract: Large conformational changes in the LID and NMP domains of adenylate kinase (AKE) are known to be key to ligand binding and catalysis, yet the order of binding events and domain motion is not well understood. Combining the multiple available structures for AKE with the energy landscape theory for protein folding, a theoretical model was developed for allostery, order of binding events, and efficient catalysis. Coarse-grained models and nonlinear normal mode analysis were used to infer that intrinsic structural fluctuations dominate LID motion, whereas ligand-protein interactions and cracking ( local unfolding) are more important during NMP motion. In addition, LID-NMP domain interactions are indispensable for efficient catalysis. LID domain motion precedes NMP domain motion, during both opening and closing. These findings provide a mechanistic explanation for the observed 1: 1: 1 correspondence between LID domain closure, NMP domain closure, and substrate turnover. This catalytic cycle has likely evolved to reduce misligation, and thus inhibition, of AKE. The separation of allosteric motion into intrinsic structural fluctuations and ligand-induced contributions can be generalized to further our understanding of allosteric transitions in other proteins. |
BibTeX:
@article{Whitford2008,
author = {Whitford, P. C. and Gosavi, S. and Onuchic, J. N.},
title = {Conformational transitions in adenylate kinase - Allosteric communication reduces misligation},
journal = {Journal Of Biological Chemistry},
year = {2008},
volume = {283},
pages = {2042--2048}
}
|
| Whitford, P.C., Noel, J.K., Gosavi, S., Schug, A., Sanbonmatsu, K. & Onuchic, J.N. (2008), "An All-Atom Structure-Based Potential for Proteins: Bridging Minimal Models with Empirical Forcefields", PROTEINS: Structure, Function, and Bioinformatics. Vol. (in press)
[BibTeX] [URL]
|
BibTeX:
@article{whitford08a,
author = {P. C. Whitford and J. K. Noel and S. Gosavi and A. Schug and K. Sanbonmatsu and J. N. Onuchic},
title = {An All-Atom Structure-Based Potential for Proteins: Bridging Minimal Models with Empirical Forcefields},
journal = {PROTEINS: Structure, Function, and Bioinformatics},
year = {2008},
volume = {(in press)},
url = {PROTEINS_AA-SB_2008.pdf}
}
|
| Finke, J.M., Jennings, P.A., Lee, J.C., Onuchic, J.N. & Winkler, J.R. (2007), "Equilibrium unfolding of the poly(glutamic acid)(20) helix", Biopolymers. Vol. 86(3), pp. 193-211.
[Abstract] [BibTeX]
|
| Abstract: The equilibrium structural ensemble of a 20-residue polyglutamic acid peptide (E-20) was studied with FRET, circular dichroism, and molecular dynamics (MD) simulations. A FRET donor, o-aminobenzamide, and acceptor, 3-nitrotyrosine, were introduced at the N- and C-termini, respectively. circular dichroisrn, steady state FRET, and time-resolved FRET measurements were employed to characterize the fraction helix and end-to-end distance under different pH conditions: pH 4 (60% alpha -helix), pH 6 (0% alpha-helix), and pH 9 (0% a -helix). At pH 4, the end-to-end distance was measured at 24 angstrom and determined to be considerably less than the 31 angstrom predicted for an alpha-helix of the same length. At pH 6 and 91 the end-to-end distance was measured at > 31 and 39 A respectively, both which are determined to be considerably greater than the 27 A predicted for a freely jointed random coil of the same length. To better understand the physical forces underlying the unusual helix-coil transition in this peptide, three theoretical MD models of E-20 were constructed: (1) a pure alpha-helix, (2) an alpha-helix with equivalent attractive intramolecular contacts, and (3) a weak alpha-helix with termini-weighted intramolecular contacts ("sticky ends"). Using MD simulations, the bent helix structure calculated from Model 3 was found to be the closest in agreement with the experimental data. (C) 2007 Wiley Periodicals, Inc. Biopolymers 86: 193-211, 2007. |
BibTeX:
@article{Finke2007,
author = {Finke, J. M. and Jennings, P. A. and Lee, J. C. and Onuchic, J. N. and Winkler, J. R.},
title = {Equilibrium unfolding of the poly(glutamic acid)(20) helix},
journal = {Biopolymers},
year = {2007},
volume = {86},
number = {3},
pages = {193--211}
}
|
| Gosavi, S., Jennings, P.A. & Onuchic, J.N. (2007), "The folding of an "average" beta-trefoil protein", Biophysical Journal. , pp. 216A-216A.
[BibTeX]
|
BibTeX:
@article{Gosavi2007,
author = {Gosavi, S. and Jennings, P. A. and Onuchic, J. N.},
title = {The folding of an "average" beta-trefoil protein},
journal = {Biophysical Journal},
year = {2007},
pages = {216A--216A}
}
|
| Hyeon, C. & Onuchic, J.N. (2007), "Mechanical control of the directional stepping dynamics of the kinesin motor", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 104, pp. 17382-17387.
[Abstract] [BibTeX]
|
| Abstract: Among the multiple steps constituting the kinesin mechanochemical cycle, one of the most interesting events is observed when kinesins move an 8-nm step from one microtubule (MT)-binding site to another. The stepping motion that occurs within a relatively short time scale (approximate to 100 mu s) is, however, beyond the resolution of current experiments. Therefore, a basic understanding to the real-time dynamics within the 8-nm step is still lacking. For instance, the rate of power stroke (or conformational change) that leads to the undocked-to-docked transition of neck-linker is not known, and the existence of a substep during the 8-nm step still remains a controversial issue in the kinesin community. By using explicit structures of the kinesin dimer and the MT consisting of 13 protofilaments, we study the stepping dynamics with varying rates of power stroke (k(p)). We estimate that k(p)(-1) <= 20 mu s to avoid a substep in an averaged time trace. For a slow power stroke with k(p)(-1) > 20 mu s, the averaged time trace shows a substep that implies the existence of a transient intermediate, which is reminiscent of a recent single-molecule experiment at high resolution. We identify the intermediate as a conformation in which the tethered head is trapped in the sideway binding site of the neighboring protofilament. We also find a partial unfolding (cracking) of the binding motifs occurring at the transition state ensemble along the pathways before binding between the kinesin and MT. |
BibTeX:
@article{Hyeon2007,
author = {Hyeon, C. and Onuchic, J. N.},
title = {Mechanical control of the directional stepping dynamics of the kinesin motor},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2007},
volume = {104},
pages = {17382--17387}
}
|
| Hyeon, C. & Onuchic, J.N. (2007), "Internal strain regulates the nucleotide binding site of the kinesin leading head", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 104(7), pp. 2175-2180.
[Abstract] [BibTeX]
|
| Abstract: In the presence of ATIP, kinesin proceeds along the protofilament of microtubule by alternated binding of two motor domains on the tubulin binding sites. Because the processivity of kinesin is much higher than other motor proteins, it has been speculated that there exists a mechanism for allosteric regulation between the two monomers. Recent experiments suggest that ATP binding to the leading head (L) domain in kinesin is regulated by the rearward strain built on the neck-linker. We test this hypothesis by explicitly modeling a C-alpha-based kinesin structure whose motor domains are bound on the tubulin binding sites. The equilibrium structures of kinesin on the microtubule show disordered and ordered neck-linker configurations for the L and trailing head, respectively. The comparison of the structures between the two heads shows that several native contacts present at the nucleotide binding site in the L are less intact than those in the binding site of the rear head. The network of native contacts obtained from this comparison provides the internal tension propagation pathway, which leads to the disruption of the nucleoticle binding site in the L. Also, using an argument based on polymer theory, we estimate the internal tension built on the neck-linker to be f approximate to 12-15 pN. Both of these conclusions support the experimental hypothesis. |
BibTeX:
@article{Hyeon2007a,
author = {Hyeon, C. and Onuchic, J. N.},
title = {Internal strain regulates the nucleotide binding site of the kinesin leading head},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2007},
volume = {104},
number = {7},
pages = {2175--2180}
}
|
| Levy, Y., Onuchic, J.N. & Wolynes, P.G. (2007), "Fly-casting in protein-DNA binding: Frustration between protein folding and electrostatics facilitates target recognition", Journal Of The American Chemical Society. Vol. 129, pp. 738-739.
[Abstract] [BibTeX]
|
| Abstract: Molecular plasticity, the key to many biomolecular self-assembly processes, and electrostatic steering, which guides proteins to DNA, are shown to be coupled and to facilitate DNA search. While protein flexibility is involved in induced-fit recognition and to a larger extent in intrinsically unstructured DNA binding proteins, we show that through a "tidal force" the electrostatic field of the DNA can induce flexibility and the partial unfolding of a two-state folding protein, thereby reducing its folding barrier and, thus, stimulating fly-casting. The protein binds DNA nonspecifically in a partially folded state and completes its folding when it binds the specific site. The interplay between fly-casting and electrostatics is observed even for weak electrostatic forces and is expected to vary with the electrostatic screening due to salt and the intrinsic folding barrier, both of which can be modulated experimentally. |
BibTeX:
@article{Levy2007,
author = {Levy, Y. and Onuchic, J. N. and Wolynes, P. G.},
title = {Fly-casting in protein-DNA binding: Frustration between protein folding and electrostatics facilitates target recognition},
journal = {Journal Of The American Chemical Society},
year = {2007},
volume = {129},
pages = {738--739}
}
|
| Liu, J., Desai, A., Onuchic, J.N. & Hwa, T. (2007), "A mechanobiochemical mechanism for monooriented chromosome oscillation in mitosis", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 104, pp. 16104-16109.
[Abstract] [BibTeX]
|
| Abstract: During mitosis, the condensed chromosomes undergo a series of spectacular oscillations after they are captured in an end-on manner by kinetochore microtubules (KMT) emanating from the spindle poles. Such oscillations are commonly attributed to tug-of-warlike mechanisms, where the mechanical force imbalance alone drives the chromosome movement. However, a large portion of the force imbalance upon the chromosome is absorbed by the kinetochore and may not drive chromosome movement directly. Mounting evidence suggests that such resistance by the kinetochores regulates the chemical reactions of KMT plus-end growth and shrinkage, which have been shown as the determinant of the chromosome antipoleward (AP) and poleward movements. Here we incorporate this important regulatory feature, propose a mechanobiochemical feedback mechanism, and apply it to the monooriented chromosome oscillation, the early stage of the series of observed chromosome oscillations. in this model, the mechanical movement of the chromosome and the local biochemical reactions at the attached kinetochore region form a feedback loop that drives the oscillation. The force imbalance exerted on the chromosomes provides a bias (via mechanically sensitive proteins) on the local biochemical reactions controlling the KMT plus-end dynamics, and the movement of the chromosome in turn changes the forces exerted on it through the experimentally supported gradient in AP force. The proposed feedback mechanism can generate oscillatory behavior that depends on the topology of the feedback loop but is largely independent of the detailed molecular mechanism. We suggest potential molecular players, whose perturbation may allow direct experimental tests of the model. |
BibTeX:
@article{Liu2007,
author = {Liu, J. and Desai, A. and Onuchic, J. N. and Hwa, T.},
title = {A mechanobiochemical mechanism for monooriented chromosome oscillation in mitosis},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2007},
volume = {104},
pages = {16104--16109}
}
|
| Mills, J.E., Whitford, P.C., Shaffer, J., Onuchic, J.N., Adams, J.A. & Jennings, P.A. (2007), "A novel disulfide bond in the SH2 domain of the C-terminal Src kinase controls catalytic activity", Journal Of Molecular Biology. Vol. 365(5), pp. 1460-1468.
[Abstract] [BibTeX]
|
| Abstract: The SH2 domain of the C-terminal Src kinase [Csk] contains a unique disulfide bond that is not present in other known SH2 domains. To investigate whether this unusual disulfide bond serves a novel function, the effects of disulfide bond formation on catalytic activity of the full-length protein and on the structure of the SH2 domain were investigated. The kinase activity of full-length Csk decreases by an order of magnitude upon formation of the disulfide bond in the distal SH2 domain. NMR spectra of the fully oxidized and fully reduced SH2 domains exhibit similar chemical shift patterns and are indicative of similar, well-defined tertiary structures. The solvent-accessible disulfide bond in the isolated SH2 domain is highly stable and far from the small lobe of the kinase domain. However, reduction of this bond results in chemical shift changes of resonances that map to a cluster of residues that extend from the disulfide bond across the molecule to a surface that is in direct contact with the small lobe of the kinase domain in the intact molecule. Normal mode analyses and molecular dynamics calculations suggest that disulfide bond formation has large effects on residues within the kinase domain, most notably within the active-site cleft. Overall, the data indicate that reversible cross-linking of two cysteine residues in the SH2 domain greatly impacts catalytic function and interdomain communication in Csk. (c) 2006 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Mills2007,
author = {Mills, J. E. and Whitford, P. C. and Shaffer, J. and Onuchic, J. N. and Adams, J. A. and Jennings, P. A.},
title = {A novel disulfide bond in the SH2 domain of the C-terminal Src kinase controls catalytic activity},
journal = {Journal Of Molecular Biology},
year = {2007},
volume = {365},
number = {5},
pages = {1460--1468}
}
|
| Schug, A. & Onuchic, J. (2007), "Symmetric mutations and their asymmetric effect on a dual-funneled energy landscape: Modelling the Rop-dimer", Biophysical Journal. , pp. 216A-216A.
[BibTeX]
|
BibTeX:
@article{Schug2007a,
author = {Schug, A. and Onuchic, J.},
title = {Symmetric mutations and their asymmetric effect on a dual-funneled energy landscape: Modelling the Rop-dimer},
journal = {Biophysical Journal},
year = {2007},
pages = {216A--216A}
}
|
| Schug, A., Whitford, P.C., Levy, Y. & Onuchic, J.N. (2007), "Mutations as trapdoors to two competing native conformations of the Rop-dimer", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 104, pp. 17674-17679.
[Abstract] [BibTeX]
|
| Abstract: Conformational transitions play a central role in regulating protein function. Structure-based models with multiple basins have been used to understand the mechanisms governing these transitions. A model able to accommodate multiple folding basins is proposed to explore the mutational effects in the folding of the Rop-dimer (Rop). In experiments, Rop mutants show unusually strong increases in folding rates with marginal effects on stability. We investigate the possibility of two competing conformations representing a parallel (P) and the wild-type antiparallel (AP) arrangement of the monomers as possible native conformations. We observe occupation of both distinct states and characterize the transition pathways. An interesting observation from the simulations is that, for equivalent energetic bias, the transition to the P basin (non-wild-type basin) shows a lower free-energy barrier. Thus, the rapid kinetics observed in experiments appear to be the result of two competing states with different kinetic behavior, triggered upon mutation by the opening of a trapdoor arising from Rop's symmetric structure. The general concept of having competing conformations for the native state goes beyond explaining Rop's mutational behaviors and can be applied to other systems. A switch between competing native structures might be triggered by external factors to allow, for example, allosteric control or signaling. |
BibTeX:
@article{Schug2007,
author = {Schug, A. and Whitford, P. C. and Levy, Y. and Onuchic, J. N.},
title = {Mutations as trapdoors to two competing native conformations of the Rop-dimer},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2007},
volume = {104},
pages = {17674--17679}
}
|
| Schultz, D., Ben Jacob, E., Onuchic, J.N. & Wolynes, P.G. (2007), "Molecular level stochastic model for competence cycles in Bacillus subtilis", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 104, pp. 17582-17587.
[Abstract] [BibTeX]
|
| Abstract: The role of stochasticity and noise in controlling genetic circuits is investigated in the context of transitions into and from competence in Bacillus subtilis. Recent experiments have demonstrated that bistability is not necessary for this function, but that the existence of one stable fixed point (vegetation) and an excitable unstable one (competence) is sufficient. Stochasticity therefore plays a crucial role in this excitation. Noise can be generated by discrete events such as RNA and protein synthesis and their degradation. We consider an alternative noise source connected with the protein binding/unbinding to the DNA. A theoretical model that includes this "nonadiabatic" mechanism appears to produce a better agreement with experiments than models where only the adiabatic limit is considered, suggesting that this nonconventional stochasticity source may be important for biological functions. |
BibTeX:
@article{Schultz2007,
author = {Schultz, D. and Ben Jacob, E. and Onuchic, J. N. and Wolynes, P. G.},
title = {Molecular level stochastic model for competence cycles in Bacillus subtilis},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2007},
volume = {104},
pages = {17582--17587}
}
|
| Schultz, D., Onuchic, J.N. & Wolynes, P.G. (2007), "Understanding stochastic simulations of the smallest genetic networks.", J Chem Phys. Vol. 126(24), pp. 245102.
[Abstract] [BibTeX]
|
| Abstract: Because genetic networks function with few molecules, such systems are better described by stochastic models than by macroscopic kinetics. Stochastic simulations of a self-regulating gene are compared with analytical solutions of the master equations, showing how the dynamics depends on the average number of proteins in the system, the repression strength, and the relative speed of the binding/unbinding and synthesis/degradation events. Steady-state and transient probability distributions for the toggle switch along with typical trajectories show that strongly repressed systems are better candidates for "good switches." |
BibTeX:
@article{Schultz2007b,
author = {Schultz, Daniel and Onuchic, Jose N. and Wolynes, Peter G.},
title = {Understanding stochastic simulations of the smallest genetic networks.},
journal = {J Chem Phys},
year = {2007},
volume = {126},
number = {24},
pages = {245102}
}
|
| Schultz, D., Onuchic, J.N. & Wolynes, P.G. (2007), "Understanding stochastic simulations of the smallest genetic networks", Journal Of Chemical Physics. Vol. 126(24)
[Abstract] [BibTeX]
|
| Abstract: Because genetic networks function with few molecules, such systems are better described by stochastic models than by macroscopic kinetics. Stochastic simulations of a self-regulating gene are compared with analytical solutions of the master equations, showing how the dynamics depends on the average number of proteins in the system, the repression strength, and the relative speed of the binding/unbinding and synthesis/degradation events. Steady-state and transient probability distributions for the toggle switch along with typical trajectories show that strongly repressed systems are better candidates for "good switches." (c) 2007 American Institute of Physics. |
BibTeX:
@article{Schultz2007a,
author = {Schultz, D. and Onuchic, J. N. and Wolynes, P. G.},
title = {Understanding stochastic simulations of the smallest genetic networks},
journal = {Journal Of Chemical Physics},
year = {2007},
volume = {126},
number = {24}
}
|
| Whitford, P.C., Miyashita, O., Levy, Y. & Onuchic, J.N. (2007), "Conformational transitions of adenylate kinase: Switching by cracking", Journal Of Molecular Biology. Vol. 366(5), pp. 1661-1671.
[Abstract] [BibTeX]
|
| Abstract: Conformational heterogeneity in proteins is known to often be the key to their function. We present a coarse grained model to explore the interplay between protein structure, folding and function which is applicable to allosteric or non-allosteric proteins. We employ the model to study the detailed mechanism of the reversible conformational transition of Adenylate Kinase (AKE) between the open to the closed conformation, a reaction that is crucial to the protein's catalytic function. We directly observe high strain energy which appears to be correlated with localized unfolding during the functional transition. This work also demonstrates that competing native interactions from the open and closed form can account for the large conformational transitions in AKE. We further characterize the conformational transitions with a new measure and demonstrate that local unfolding may be due, in part, to competing intra-protein interactions. (c) 2006 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Whitford2007,
author = {Whitford, P. C. and Miyashita, O. and Levy, Y. and Onuchic, J. N.},
title = {Conformational transitions of adenylate kinase: Switching by cracking},
journal = {Journal Of Molecular Biology},
year = {2007},
volume = {366},
number = {5},
pages = {1661--1671}
}
|
| Yang, S.C., Onuchic, J.N., Garcia, A.E. & Levine, H. (2007), "Folding time predictions from all-atom replica exchange simulations", Journal Of Molecular Biology. Vol. 372(3), pp. 756-763.
[Abstract] [BibTeX]
|
| Abstract: We present an approach to predicting the folding time distribution from all-atom replica exchange simulations. This is accomplished by approximating the multidimensional folding process as stochastic reaction-coordinate dynamics for which effective drift velocities and diffusion coefficients are determined from the short-time replica exchange simulations. Our approach is applied to the folding of the second beta-hairpin of the B domain of protein G. The folding time prediction agrees quite well with experimental measurements. Therefore, we have in hand a fast numerical tool for calculating the folding kinetic properties from all-atom "first principles" models. |
BibTeX:
@article{Yang2007,
author = {Yang, S. C. and Onuchic, J. N. and Garcia, A. E. and Levine, H.},
title = {Folding time predictions from all-atom replica exchange simulations},
journal = {Journal Of Molecular Biology},
year = {2007},
volume = {372},
number = {3},
pages = {756--763}
}
|
| Chavez, L.L., Gosavi, S., Jennings, P.A. & Onuchic, J.N. (2006), "Multiple routes lead to the native state in the energy landscape of the beta-trefoil family", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 103(27), pp. 10254-10258.
[Abstract] [BibTeX]
|
| Abstract: In general, the energy landscapes of real proteins are sufficiently well designed that the depths of local energetic minima are small compared with the global bias of the native state. Because of the funneled nature of energy landscapes, models that lack energetic frustration have been able to capture the main structural features of the transition states and intermediates found in experimental studies of both small and large proteins. In this study we ask: Are the experimental differences in folding mechanisms among members of a particular structural family due to local topological constraints that deviate from the tertiary fold common to the family? The beta-trefoil structural family members IL-1 beta, hisactophilin, and acidic/basic FGFs were chosen to address this question. It has been observed that the topological landscape of the beta-trefoils allows for the population of diverse, geometrically disconnected routes that provide energetically similar but structurally distinct ways for this family to fold. Small changes in topology or energetics can alter the preferred route. Taken together, these results indicate that the global fold of the beta-trefoil family determines the energy landscape but that the routes accessed on that landscape might differ as a result of functional requirements of the individual family members. |
BibTeX:
@article{Chavez2006,
author = {Chavez, L. L. and Gosavi, S. and Jennings, P. A. and Onuchic, J. N.},
title = {Multiple routes lead to the native state in the energy landscape of the beta-trefoil family},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2006},
volume = {103},
number = {27},
pages = {10254--10258}
}
|
| Gosavi, S., Chavez, L.L., Jennings, P.A. & Onuchic, J.N. (2006), "Topological frustration and the folding of interleukin-1 beta", Journal Of Molecular Biology. Vol. 357(3), pp. 986-996.
[Abstract] [BibTeX]
|
| Abstract: The cytokine, iriterleukin-1 beta (IL-1 beta), adopts a beta-trefoil fold. It is known to be much slower folding than similarly sized proteins, despite having a low contact order. Proteins are sufficiently well designed that their folding is not dominated by local energetic traps. Therefore, protein models that encode only the folded structure and are energetically unfrustrated (GO-type), can capture the essentials of the folding routes. We investigate the folding thermodynamics of IL-1 beta using such a model and molecular dynamics (MD) simulations. We develop an enhanced sampling technique (a modified multicanonical method) to overcome the sampling problem caused by the slow folding. We find that IL-1 beta has a broad and high free energy barrier. In addition, the protein fold causes intermediate unfolding and refolding of some native contacts within the protein along the folding trajectory. This "backtracking" occurs around the barrier region. Complex folds like the beta-trefoil fold and functional loops like the beta-bulge of IL-1 beta can make some of the configuration space unavailable to the protein and cause topological frustration. (c) 2005 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Gosavi2006,
author = {Gosavi, S. and Chavez, L. L. and Jennings, P. A. and Onuchic, J. N.},
title = {Topological frustration and the folding of interleukin-1 beta},
journal = {Journal Of Molecular Biology},
year = {2006},
volume = {357},
number = {3},
pages = {986--996}
}
|
| Levy, Y. & Onuchic, J.N. (2006), "Mechanisms of protein assembly: Lessons from minimalist models", Accounts Of Chemical Research. Vol. 39, pp. 135-142.
[Abstract] [BibTeX]
|
| Abstract: Many cellular functions rely on interactions among proteins and between proteins and nucleic acids. The limited success of binding predictions may suggest that the physical and chemical principles of protein binding have to be revisited to correctly capture the essence of protein recognition. In this Account, we discuss the power of reduced models to study the physics of protein assembly. Since energetic frustration is sufficiently small, native topology-based models, which correspond to perfectly unfrustrated energy landscapes, have shown that binding mechanisms are robust and governed primarily by the protein's native topology. These models impressively capture many of the binding characteristics found in experiments and highlight the fundamental role of flexibility in binding. The essential role of solvent molecules and electrostatic interactions in binding is also discussed. Despite the success of the minimally frustrated models to describe the dynamics and mechanisms of binding, the actual degree of frustration has to be explored to quantify the capacity of a protein to bind specifically to other proteins. We have found that introducing mutations can significantly reduce specificity by introducing an additional binding mode. Deciphering and quantifying the key ingredients for biological self-assembly is invaluable to reading out genomic sequences and understanding cellular interaction networks. |
BibTeX:
@article{Levy2006a,
author = {Levy, Y. and Onuchic, J. N.},
title = {Mechanisms of protein assembly: Lessons from minimalist models},
journal = {Accounts Of Chemical Research},
year = {2006},
volume = {39},
pages = {135--142}
}
|
| Levy, Y. & Onuchic, J.N. (2006), "Water mediation in protein folding and molecular recognition", Annual Review Of Biophysics And Biomolecular Structure. Vol. 35, pp. 389-415.
[Abstract] [BibTeX]
|
| Abstract: Water is essential for life in many ways, and without it biomolecules might no longer truly be biomolecules. In particular, water is important to the structure, stability dynamics, and function of biological macromolecules. In protein folding, water mediates the collapse of the chain and the search for the native topology through a funneled energy landscape. Water actively participates in molecular recognition by mediating the interactions between binding partners and contributes to either enthalpic or entropic stabilization. Accordingly, water must be included in recognition and structure prediction codes to capture specificity. Thus water should not be treated as an inert environment, but rather as an integral and active component of biomolecular systems, where it has both dynamic and structural roles. Focusing on water sheds light on the physics and function of biological machinery and self-assembly and may advance our understanding of the natural design of proteins and nucleic acids. |
BibTeX:
@article{Levy2006,
author = {Levy, Y. and Onuchic, J. N.},
title = {Water mediation in protein folding and molecular recognition},
journal = {Annual Review Of Biophysics And Biomolecular Structure},
year = {2006},
volume = {35},
pages = {389--415}
}
|
| Liu, J. & Onuchic, J.N. (2006), "A driving and coupling "Pac-Man" mechanism for chromosome poleward translocation in anaphase A", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 103(49), pp. 18432-18437.
[Abstract] [BibTeX]
|
| Abstract: During mitosis, chromatid harnesses its kinetochore translocation at the depolymerizing microtubule ends for its poleward movement in anaphase A. The force generation mechanism for such movement remains unknown. Analysis of the current experimental results shows that the bending energy release from the bound tubulin subunits alone cannot provide sufficient driving force. Additional contribution from effective electrostatic attractions between the kinetochore and the microtubule is needed for kinetochore translocation. Interestingly, as the kinetochore moves to inside the microtubule, the microtubule tip is free to bend outward so that the instantaneous distance between the kinetochore and the microtubule tip is much closer than the rest of the microtubule. This close contact yields much larger electrostatic attraction than that from the rest of the microtubule under physiological ionic conditions. As a result, the effective electrostatic interaction hinders the further kinetochore poleward translocation until the microtubule tip dissociates. Thus, the kinetochore translocation is strongly coupled at the depolymerizing microtubule end. This driving-coupling mechanism indicates that the kinetochore velocity is largely controlled by the microtubule dissociation rate, which explains the insensitivity of kinetochore velocity to its viscous drag and the large redundancy in its stalling force. |
BibTeX:
@article{Liu2006,
author = {Liu, J. and Onuchic, J. N.},
title = {A driving and coupling "Pac-Man" mechanism for chromosome poleward translocation in anaphase A},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2006},
volume = {103},
number = {49},
pages = {18432--18437}
}
|
| Okazaki, K., Koga, N., Takada, S., Onuchic, J.N. & Wolynes, P.G. (2006), "Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: Structure-based molecular dynamics simulations", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 103(32), pp. 11844-11849.
[Abstract] [BibTeX]
|
| Abstract: Biomolecules often undergo large-amplitude motions when they bind or release other molecules. Unlike macroscopic machines, these biomolecular machines can partially disassemble (unfold) and then reassemble (fold) during such transitions. Here we put forward a minimal structure-based model, the "multiple-basin model," that can directly be used for molecular dynamics simulation of even very large biomolecular systems so long as the endpoints of the conformational change are known. We investigate the model by simulating large-scale motions of four proteins: glutamine-binding protein, S100A6, dihydrofolate reductase, and HIV-1 protease. The mechanisms of conformational transition depend on the protein basin topologies and change with temperature near the folding transition. The conformational transition rate varies linearly with driving force over a fairly large range. This linearity appears to be a consequence of partial unfolding during the conformational transition. |
BibTeX:
@article{Okazaki2006,
author = {Okazaki, K. and Koga, N. and Takada, S. and Onuchic, J. N. and Wolynes, P. G.},
title = {Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: Structure-based molecular dynamics simulations},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2006},
volume = {103},
number = {32},
pages = {11844--11849}
}
|
| Onuchic, J.N., Kobayashi, C., Miyashita, O., Jennings, P. & Baldridge, K.K. (2006), "Exploring biomolecular machines: energy landscape control of biological reactions", Philosophical Transactions Of The Royal Society B-Biological Sciences. Vol. 361(1472), pp. 1439-1443.
[Abstract] [BibTeX]
|
| Abstract: For almost 15 years, our Pathway model has been the most powerful model in terms of predicting the tunnelling mechanism for electron transfer (ET) in biological systems, particularly proteins. Going beyond the conventional Pathway models, we have generalized our method to understand how protein dynamics modulate not only the Franck-Condon factor, but also the tunnelling matrix element. We have demonstrated that when interference among pathways modulates the electron tunnelling interactions in proteins (particularly destructive interference), dynamical effects are of critical importance. Tunnelling can be controlled by protein conformations that lie far from equilibrium-those that minimize the effect of destructive interference during tunnelling, for example. In the opposite regime, electron tunnelling is mediated by one (or a few) constructively interfering pathway tubes and dynamical effects are modest. This new mechanism for dynamical modulation of the ET rate has been able to explain and/or predict several rates that were later confirmed by experiment. However, thermal fluctuations can also affect these molecular machines in many other ways. For example, we show how global transformations, which control protein functions such as allostery, may involve large-scale motion and possibly partial unfolding during the reaction event. |
BibTeX:
@article{Onuchic2006,
author = {Onuchic, J. N. and Kobayashi, C. and Miyashita, O. and Jennings, P. and Baldridge, K. K.},
title = {Exploring biomolecular machines: energy landscape control of biological reactions},
journal = {Philosophical Transactions Of The Royal Society B-Biological Sciences},
year = {2006},
volume = {361},
number = {1472},
pages = {1439--1443}
}
|
| Simler, B.R., Levy, Y., Onuchic, J.N. & Matthews, C.R. (2006), "The folding energy landscape of the dimerization domain of Escherichia coli trp repressor: A joint experimental and theoretical investigation", Journal Of Molecular Biology. Vol. 363(1), pp. 262-278.
[Abstract] [BibTeX]
|
| Abstract: Enhanced structural insights into the folding energy landscape of the N-terminal dimerization. domain of Escherichia coli tryptophan repressor, [2-66](2) TR, were obtained from a combined experimental and theoretical analysis of its equilibrium folding reaction. Previous studies have shown that the three intertwined helices in [2-66](2) TR are sufficient to drive the formation of a stable dimer for the full-length protein, [2107](2) TR. The monomeric and dimeric folding intermediates that appear during the folding reactions of [2-66](2) TR have counterparts in the folding mechanism of the full-length protein. The equilibrium unfolding energy surface on which the folding and dimerization reactions occur for [2-66](2) TR was examined with a combination of native-state hydrogen exchange analysis, pepsin digestion and matrix-assisted laser/ desorption mass spectrometry performed at several concentrations of protein and denaturant. Peptides corresponding to all three helices in [2-66](2) TR show multi-layered protection patterns consistent with the relative stabilities of the climeric and monomeric folding intermediates. The observation of protection exceeding that offered by the dimeric intermediate in segments from all three helices implies that a segment-swapping mechanism may be operative in the monomeric intermediate. Protection greater than that expected from the global stability for a single amide hydrogen in a peptide from the C-hehx possibly and another from the A-helix may reflect nonrandom structure, possibly a precursor for segment swapping, in the ureadenatured state. Native topology-based model simulations that correspond to a funnel energy landscape capture both the monomeric and dimeric intermediates suggested by the HX MS data and provide a rationale for the progressive acquisition of secondary structure in their conformational ensembles. (c) 2006 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Simler2006,
author = {Simler, B. R. and Levy, Y. and Onuchic, J. N. and Matthews, C. R.},
title = {The folding energy landscape of the dimerization domain of Escherichia coli trp repressor: A joint experimental and theoretical investigation},
journal = {Journal Of Molecular Biology},
year = {2006},
volume = {363},
number = {1},
pages = {262--278}
}
|
| Yang, S.C., Onuchic, J.N. & Levine, H. (2006), "Effective stochastic dynamics on a protein folding energy landscape", Journal Of Chemical Physics. Vol. 125(5)
[Abstract] [BibTeX]
|
| Abstract: We present an approach to protein folding kinetics using stochastic reaction-coordinate dynamics, in which the effective drift velocities and diffusion coefficients are determined from microscopic simulation data. The resultant Langevin equation can then be used to directly simulate the folding process. Here, we test this approach by applying it to a toy two-state dynamical system and to a funnellike structure-based (G (o) over bar -type) model. The folding time predictions agree very well with full simulation results. Therefore, we have in hand a fast numerical tool for calculating the folding kinetic properties, even when full simulations are not feasible. In addition, the local drift and diffusion coefficients provide an alternative way to compute the free energy profile in cases where only local sampling can be achieved. (c) 2006 American Institute of Physics. |
BibTeX:
@article{Yang2006,
author = {Yang, S. C. and Onuchic, J. N. and Levine, H.},
title = {Effective stochastic dynamics on a protein folding energy landscape},
journal = {Journal Of Chemical Physics},
year = {2006},
volume = {125},
number = {5}
}
|
| Cho, S.S., Levy, Y., Onuchic, J.N. & Wolynes, P.G. (2005), "Overcoming residual frustration in domain-swapping: the roles of disulfide bonds in dimerization and aggregation", Physical Biology. Vol. 2(2), pp. S44-S55.
[Abstract] [BibTeX]
|
| Abstract: The prevalence of domain-swapping in nature is a manifestation of the principle of minimal frustration in that the interactions designed by evolution to stabilize the protein are also involved in this mode of binding. We previously demonstrated that the Symmetrized-Go potential accurately predicts the experimentally observed domain-swapped structure of Eps8 based solely on the structure of the monomer. There can be, however, multiple modes of domain-swapping, reflecting a higher level of frustration, which is a consequence of symmetry. The human prion and cyanovirin-N are too frustrated to form unique domain-swapped structures on the basis of the Symmetrized-Go potential. However, supplementing the completely symmetric model with intermolecular and intramolecular disulfide bonds in the prion and cyanovirin-N proteins, respectively, yielded unique domain-swapped structures with a remarkable similarity to the experimentally observed ones. These results suggest that the disulfide bonds may sometimes be critical in overcoming the intrinsic frustration of the symmetrized energy landscapes for domain-swapping. We also discuss the implications of intermolecular disulfide bonds in the formation of mammalian prion aggregates. |
BibTeX:
@article{Cho2005,
author = {Cho, S. S. and Levy, Y. and Onuchic, J. N. and Wolynes, P. G.},
title = {Overcoming residual frustration in domain-swapping: the roles of disulfide bonds in dimerization and aggregation},
journal = {Physical Biology},
year = {2005},
volume = {2},
number = {2},
pages = {S44--S55}
}
|
| Finke, J.M. & Onuchic, J.N. (2005), "Equilibrium and kinetic folding pathways of a TIM barrel with a funneled energy landscape", Biophysical Journal. Vol. 89(1), pp. 488-505.
[Abstract] [BibTeX]
|
| Abstract: The role of native contact topology in the folding of a TIM barrel model based on the alpha-subunit of tryptophan synthase (alpha TS) from Salmonella typhimurium (Protein Data Bank structure 1BKS) was studied using both equilibrium and kinetic simulations. Equilibrium simulations of alpha TS reveal the population of two intermediate ensembles, I-1 and I-2, during unfolding/refolding at the folding temperature, T-f=335 K. Equilibrium intermediate I-1 demonstrates discrete structure in regions alpha(0)-beta(6) whereas intermediate I-2 is a loose ensemble of states with N-terminal structure varying from at least beta(1)-beta(3) (denoted I-2A) to alpha(0)-beta(4) at most (denoted I-2B). The structures of I-1 and I-2 match well with the two intermediate states detected in equilibrium folding experiments of Escherichia coli alpha TS. Kinetic folding simulations of alpha TS reveal the sequential population of four intermediate ensembles, I-120Q, I-200Q, I-300Q, and I-360Q, during refolding. Kinetic intermediates I-120Q, I-200Q, and I-300Q are highly similar to equilibrium alpha TS intermediates I-2A, I-2B, and I-1, respectively, consistent with kinetic experiments on alpha TS from E. coli. A small population (similar to 10%) of kinetic trajectories are trapped in the I-120Q intermediate ensemble and require a slow and complete unfolding step to properly refold. Both the on-pathway and off-pathway I-120Q intermediates show structure in beta(1)-beta(3), which is also strikingly consistent with kinetic folding experiments of alpha TS. In the off-pathway intermediate I-120Q, helix alpha(2) is wrapped in a nonnative chiral arrangement around strand beta(3), sterically preventing the subsequent folding step between beta(3) and beta(4). These results demonstrate the success of combining kinetic and equilibrium simulations of minimalist protein models to explore TIM barrel folding and the folding of other large proteins. |
BibTeX:
@article{Finke2005,
author = {Finke, J. M. and Onuchic, J. N.},
title = {Equilibrium and kinetic folding pathways of a TIM barrel with a funneled energy landscape},
journal = {Biophysical Journal},
year = {2005},
volume = {89},
number = {1},
pages = {488--505}
}
|
| Garcia, A.E. & Onuchic, J.N. (2005), "Folding a protein in the computer: Reality or hope?", Structure. Vol. 13, pp. 497-498.
[Abstract] [BibTeX]
|
| Abstract: In this issue of Structure, Herges and Wenzel (2005) describe a structure-based force field that, when combined with a stochastic optimization method, a modified basin hopping method, can fold a-helical proteins. Although limited to a-helical structures, this approach further supports that predicting protein structures in a computer is becoming a reality. |
BibTeX:
@article{Garcia2005,
author = {Garcia, A. E. and Onuchic, J. N.},
title = {Folding a protein in the computer: Reality or hope?},
journal = {Structure},
year = {2005},
volume = {13},
pages = {497--498}
}
|
| Hornos, J.E.M., Schultz, D., Innocentini, G.C.P., Wang, J., Walczak, A.M., Onuchic, J.N. & Wolynes, P.G. (2005), "Self-regulating gene: an exact solution.", Phys Rev E Stat Nonlin Soft Matter Phys. Vol. 72(5 Pt 1), pp. 051907.
[Abstract] [BibTeX]
|
| Abstract: An exact steady-state solution of the stochastic equations governing the behavior of a gene regulated by a self-generated proteomic atmosphere is presented. The solutions depend on an adiabaticity parameter measuring the relative rate of DNA-protein unbinding and protein degradation. The steady-state solution reveals deviations from the commonly used Ackers et al approximation based on the equilibrium law of mass action, allowing anticooperative behavior in the "nonadiabatic" limit of slow binding and unbinding rates. Noise from binding and unbinding events dominates the shot noise of protein synthesis and degradation up to quite high values of the adiabaticity parameter. |
BibTeX:
@article{Hornos2005a,
author = {Hornos, J. E. M. and Schultz, D. and Innocentini, G. C. P. and Wang, J. and Walczak, A. M. and Onuchic, J. N. and Wolynes, P. G.},
title = {Self-regulating gene: an exact solution.},
journal = {Phys Rev E Stat Nonlin Soft Matter Phys},
year = {2005},
volume = {72},
number = {5 Pt 1},
pages = {051907}
}
|
| Hornos, J.E.M., Schultz, D., Innocentini, G.C.P., Wang, J., Walczak, A.M., Onuchic, J.N. & Wolynes, P.G. (2005), "Self-regulating gene: An exact solution", Physical Review E. Vol. 72(5)
[Abstract] [BibTeX]
|
| Abstract: An exact steady-state solution of the stochastic equations governing the behavior of a gene regulated by a self-generated proteomic atmosphere is presented. The solutions depend on an adiabaticity parameter measuring the relative rate of DNA-protein unbinding and protein degradation. The steady-state solution reveals deviations from the commonly used Ackers approximation based on the equilibrium law of mass action, allowing anticooperative behavior in the "nonadiabatic" limit of slow binding and unbinding rates. Noise from binding and unbinding events dominates the shot noise of protein synthesis and degradation up to quite high values of the adiabaticity parameter. |
BibTeX:
@article{Hornos2005,
author = {Hornos, J. E. M. and Schultz, D. and Innocentini, G. C. P. and Wang, J. and Walczak, A. M. and Onuchic, J. N. and Wolynes, P. G.},
title = {Self-regulating gene: An exact solution},
journal = {Physical Review E},
year = {2005},
volume = {72},
number = {5}
}
|
| Levy, Y., Cho, S.S., Onuchic, J.N. & Wolynes, P.G. (2005), "A survey of flexible protein binding mechanisms and their transition states using native topology based energy landscapes", Journal Of Molecular Biology. Vol. 346, pp. 1121-1145.
[Abstract] [BibTeX]
|
| Abstract: Many cellular functions rely on interactions between protein pairs and higher oligomers. We have recently shown that binding mechanisms are robust and owing to the minimal frustration principle, just as for protein folding, are governed primarily by the protein's native topology, which is characterized by the network of non-covalent residue-residue interacdons. The detailed binding mechanisms of nine dimers, a trimer, and a tetramer, each involving different degrees of flexibility and plasticity during assembly, are surveyed here using a model that is based solely on the protein topology, having a perfectly funneled energy landscape. The importance of flexibility in binding reactions is manifested by the fly-casting effect, which is diminished in magnitude when protein flexibility is removed. Many of the grosser and finer structural aspects of the various binding mechanisms (including binding of pre-folded monomers, binding of intrinsically unfolded monomers, and binding by domain-swapping) predicted by the native topology based landscape model are consistent with the mechanisms found in the laboratory. An asymmetric binding mechanism is often observed for the formation of the symmetric homodimers where one monomer is more structured at the binding transition state and serves as a template for the folding of the other monomer. phi values were calculated to show how the structure of the binding transition state ensemble would be manifested in protein engineering studies. For most systems, the simulated phi values are reasonably correlated with the available experimental values. This agreement suggests that the overall binding mechanism and the nature of the binding transition state ensemble can be understood from the network of interactions that stabilize the native fold. The phi values for the formation of an antibody-antigen complex indicate a possible role for solvation. of the interface in biomolecular association of large rigid proteins. (C) 2005 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Levy2005a,
author = {Levy, Y. and Cho, S. S. and Onuchic, J. N. and Wolynes, P. G.},
title = {A survey of flexible protein binding mechanisms and their transition states using native topology based energy landscapes},
journal = {Journal Of Molecular Biology},
year = {2005},
volume = {346},
pages = {1121--1145}
}
|
| Levy, Y., Cho, S.S., Shen, T., Onuchic, J.N. & Wolynes, P.G. (2005), "Symmetry and frustration in protein energy landscapes: A near degeneracy resolves the Rop dimer-folding mystery", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 102(7), pp. 2373-2378.
[Abstract] [BibTeX]
|
| Abstract: Protein folding has become one of the best understood biochemical reactions from a kinetic viewpoint. The funneled energy landscape, a consequence of the minimal frustration achieved by evolution in sequences, explains how most proteins fold efficiently and robustly to their functional structure and allows robust prediction of folding kinetics. The folding of Rop (repressor of primer) dimer is exceptional because some of its mutants with a redesigned hydrophobic core both fold and unfold much faster than the WT protein, which seems to conflict with a simple funneled energy landscape for which topology mainly determines the kinetics. We propose that the mystery of Rop folding can be unraveled by assuming a double-funneled energy landscape on which there are two basins that correspond to distinct but related topological structures. Because of the near symmetry of the molecule, mutations can cause a conformational switch to a nearly degenerate yet distinct topology or lead to a mixture of both topologies. The topology predicted to have the lower free-energy barrier height for folding was further found by all-atom modeling to give a better structural fit for those mutants with the extreme folding and unfolding rates. Thus, the non-Hammond effects can be understood within energy-landscape theory if there are in fact two different but nearly degenerate structures for Rop. Mutations in symmetric and regular structures may give rise to frustration and thus result in degeneracy. |
BibTeX:
@article{Levy2005,
author = {Levy, Y. and Cho, S. S. and Shen, T. and Onuchic, J. N. and Wolynes, P. G.},
title = {Symmetry and frustration in protein energy landscapes: A near degeneracy resolves the Rop dimer-folding mystery},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2005},
volume = {102},
number = {7},
pages = {2373--2378}
}
|
| Miyashita, O., Okamura, M.Y. & Onuchic, J.N. (2005), "Interprotein electron transfer from cytochrome c(2) to photosynthetic reaction center: Tunneling across an aqueous interface", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 102(10), pp. 3558-3563.
[Abstract] [BibTeX]
|
| Abstract: Interprotein electron transfer (ET) reactions play an important role in biological energy conversion processes. One of these reactions, the ET between cytochrome c(2) (cyt) and reaction center from photosynthetic bacteria, is the focus of this theoretical study. The changes in the ET rate constant at fixed distances during the association process were calculated as the cyt moved from the electrostatically stabilized encounter complex to the bound state having short range van der Waals contacts in the tunneling region. Multiple conformations of the protein were generated by molecular dynamics simulations including explicit water molecules. For each of these conformations, the ET rate was calculated by using the Pathways model. The ET rate increased smoothly as the cyt approached from the encounter complex to the bound state, with a tunneling decay factor beta = 1.1 angstrom(-1). This relatively efficient coupling between redox centers is due to the ability of interfacial water molecules to form multiple strong hydrogen bonding pathways connecting tunneling pathways on the surfaces of the two proteins. The ET rate determined for the encounter complex ensemble of states is only about a factor of 100 slower than that of the bound state (tau = 100 mu s, compared with 1 mu s), because of fluctuations of the cyt within the encounter complex ensemble through configurations having strong tunneling pathways. The ET rate for the encounter complex is in agreement with rates observed in mutant reaction centers modified to remove shortrange hydrophobic interactions, suggesting that in this case, ET occurs within the solvent-separated, electrostatically stabilized encounter complex. |
BibTeX:
@article{Miyashita2005,
author = {Miyashita, O. and Okamura, M. Y. and Onuchic, J. N.},
title = {Interprotein electron transfer from cytochrome c(2) to photosynthetic reaction center: Tunneling across an aqueous interface},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2005},
volume = {102},
number = {10},
pages = {3558--3563}
}
|
| Miyashita, O., Wolynes, P.G. & Onuchic, J.N. (2005), "Simple energy landscape model for the kinetics of functional transitions in proteins", Journal Of Physical Chemistry B. Vol. 109(5), pp. 1959-1969.
[Abstract] [BibTeX]
|
| Abstract: It is evident that protein conformational transitions play important roles in biological machinery; however, detailed pictures of these transition processes capable of making kinetic prediction are not yet available. For a full description of these transitions, we first need to describe kinematically movements between stable states. Then, more importantly, a free energy profile associated with the conformational change needs to be obtained. Recently, a new model to describe the energy landscape of protein conformational changes was applied to the conformational transition of adenylate kinase [Miyashita, O.; Onuchic, J. N.; Wolynes, P. G. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 12570-12575]. In this model, the conformational change coupled to the ligand binding is described as a switching between two energy surfaces that correspond to ligand bound and unbound states. The nonlinearity of the protein conformational changes is described through an iterative usage of normal mode calculations. In addition, another kind of nonlinearity enters the dynamics of the conformational transitions due to cracking, or partial unfolding, which may occur during the conformational transitions. The consequences of this theoretical model are explored in greater detail. An improved model for the cracking that includes the cooperativity of the partial unfolding in analogy to nucleation is introduced. |
BibTeX:
@article{Miyashita2005a,
author = {Miyashita, O. and Wolynes, P. G. and Onuchic, J. N.},
title = {Simple energy landscape model for the kinetics of functional transitions in proteins},
journal = {Journal Of Physical Chemistry B},
year = {2005},
volume = {109},
number = {5},
pages = {1959--1969}
}
|
| Roy, M., Chavez, L.L., Finke, J.M., Heidary, D.K., Onuchic, J.N. & Jennings, P.A. (2005), "The native energy landscape for interleukin-1 beta. Modulation of the population ensemble through native-state topology", Journal Of Molecular Biology. Vol. 348(2), pp. 335-347.
[Abstract] [BibTeX]
|
| Abstract: A minimalist Go-model, with no energetic frustration in the native conformation, has been shown to describe accurately the folding pathway of the beta-trefoil protein, interleukin-1 beta (IL-1 beta). While it appears that these models successfully model transition states and intermediates between the unfolded and native ensembles, it is unclear how accurately they capture smaller yet biologically relevant, structural changes within the native ensemble after energetic perturbation. Here, we address the following questions. Can a simple Go-model of interleukin-1 beta, based on native topology, describe changes in structural properties of the native ensemble as the protein stability is changed? Or is it necessary to include a more explicit representation of atoms, electrostatic, hydrogen bonding, and van der Waals forces to describe these changes? The native ensemble of IL-1 beta was characterized using a variety of experimental probes under native (0 M NaCl, guanidine hydrochloride (Gdn-HCl)), moderately destabilized (0 M NaCl, 0.8 M Gdn-HCl), and in moderate salt concentration (0.8 M NaCl, 0 M Gdn-HCl). Heteronuclear H-1-N-15 nuclear Overhauser effect spectroscopy (NOESY) and heteronuclear single quantum correlation (HSQC) NMR spectra confirmed that the P-trefoil global fold was largely intact under these three conditions. However, 25 of the 153 residues throughout the chain did demonstrate C-13 and H-1-N-15 chemical shifts when perturbed with 0.8 M NaCl or Gdn-HCl. Despite large differences in protection factors from solvent hydrogen-deuterium exchange for all residues between stable (0 M Gdn-HCl) and destabilized (0.8 M Gdn-HCl) IL-1 beta, no difference in steady-state N-15-H-1 NOE enhancements were measured. Thus, the chemical shifts correlate with a global but limited increase in residue flexibility in the presence of Gdn-HCl. Minimalist simulations highlight the regions of greatest position shift between native and 0.8 M Gdn-HCl, which were determined experimentally. This correlation demonstrates that structural changes within the native ensemble of IL-1 beta are, at least partially, governed by the principle of minimal energetic frustration. (c) 2005 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Roy2005,
author = {Roy, M. and Chavez, L. L. and Finke, J. M. and Heidary, D. K. and Onuchic, J. N. and Jennings, P. A.},
title = {The native energy landscape for interleukin-1 beta. Modulation of the population ensemble through native-state topology},
journal = {Journal Of Molecular Biology},
year = {2005},
volume = {348},
number = {2},
pages = {335--347}
}
|
| Suzuki, Y. & Onuchic, J.N. (2005), "Modeling the interplay between geometrical and energetic effects in protein folding", Journal Of Physical Chemistry B. Vol. 109(34), pp. 16503-16510.
[Abstract] [BibTeX]
|
| Abstract: A theoretical framework is constructed with the aid of a free-energy functional method that is capable of describing the interplay between geometrical and energetic effects on protein folding. In this paper, we generalize a free-energy functional model based on polymer theory to make it more appropriate for comparison with protein folding simulations and experiments. This generalization is made by introducing cooperativity into the configurational entropy and the internal energy. Modifications to configurational entropy enable the model to account for the loop-loop interactions, a contribution neglected in the original model. Modifications to the internal energy introduce many-body corrections, which are needed to establish quantitative contact to simulations as well as experimental observations. To demonstrate the efficiency of the modified analytical model, we compare our results with C alpha structure-based (G $$(o) over bar) model simulations of chymotrypsin inhibitor II and the SH3 domain of src. |
BibTeX:
@article{Suzuki2005,
author = {Suzuki, Y. and Onuchic, J. N.},
title = {Modeling the interplay between geometrical and energetic effects in protein folding},
journal = {Journal Of Physical Chemistry B},
year = {2005},
volume = {109},
number = {34},
pages = {16503--16510}
}
|
| Walczak, A.M., Onuchic, J.N. & Wolynes, P.G. (2005), "Absolute rate theories of epigenetic stability", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 102, pp. 18926-18931.
[Abstract] [BibTeX]
|
| Abstract: Spontaneous switching events in most characterized genetic switches are rare, resulting in extremely stable epigenetic properties. We show how simple arguments lead to theories of the rate of such events much like the absolute rate theory of chemical reactions corrected by a transmission factor. Both the probability of the rare cellular states that allow epigenetic escape and the transmission factor depend on the rates of DNA binding and unbinding events and on the rates of protein synthesis and degradation. Different mechanisms of escape from the stable attractors occur in the nonadiabatic, weakly adiabatic, and strictly adiabatic regimes, characterized by the relative values of those input rates. |
BibTeX:
@article{Walczak2005,
author = {Walczak, A. M. and Onuchic, J. N. and Wolynes, P. G.},
title = {Absolute rate theories of epigenetic stability},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2005},
volume = {102},
pages = {18926--18931}
}
|
| Wong, L., Lieser, S.A., Miyashita, O., Miller, M., Tasken, K., Onuchic, J.N., Adams, J.A., Woods, V.L. & Jennings, P.A. (2005), "Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation", Journal Of Molecular Biology. Vol. 351(1), pp. 131-143.
[Abstract] [BibTeX]
|
| Abstract: The C-terminal Src kinase (Csk) phosphorylates and down-regulates Src family tyrosine kinases. The Csk-binding protein (Cbp) localizes Csk close to its substrates at the plasma membrane, and increases the specific activity of the kinase. To investigate this long-range catalytic effect, the phosphorylation of Src and the conformation of Csk were investigated in the presence of a high-affinity phosphopepticle derived from Cbp. This peptide binds tightly to the SH2 domain and enhances Src recognition (lowers Km) by increasing the apparent phosphoryl transfer rate in the Csk active site, a phenomenon detected in rapid quench flow experiments. Previous studies demonstrated that the regulation of Csk activity is linked to conformational changes in the enzyme that can be probed with hydrogen-deuterium exchange methods. We show that the Cbp peptide impacts deuterium incorporation into its binding partner (the SH2 domain), and into the SH2-kinase linker and several sequences in the kinase domain, including the glycine-rich loop in the active site. These findings, along with computational data from normal mode analyses, suggest that the SH2 domain moves in a cantilever fashion with respect to the small lobe of the kinase domain, ordering the active site for catalysis. The binding of a small Cbp-derived peptide to the SH2 domain of Csk modifies these motions, enhancing Src recognition. (c) 2005 Published by Elsevier Ltd. |
BibTeX:
@article{Wong2005,
author = {Wong, L. and Lieser, S. A. and Miyashita, O. and Miller, M. and Tasken, K. and Onuchic, J. N. and Adams, J. A. and Woods, V. L. and Jennings, P. A.},
title = {Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation},
journal = {Journal Of Molecular Biology},
year = {2005},
volume = {351},
number = {1},
pages = {131--143}
}
|
| Yang, S.C., Levine, H. & Onuchic, J.N. (2005), "Protein oligomerization through domain swapping: Role of inter-molecular interactions and protein concentration", Journal Of Molecular Biology. Vol. 352(1), pp. 202-211.
[Abstract] [BibTeX]
|
| Abstract: Domain swapping has been shown to be an important mechanism controlling multiprotein assembly and has been suggested recently as a possible mechanism underlying protein aggregation. Understanding oligomerization via domain swapping is therefore of theoretical and practical importance. By using a symmetrized structure-based (GO) model, we demonstrate that in the free-energy landscape of domain swapping, a large free-energy barrier separates monomeric and domain-swapped dimeric configurations. We investigate the effect of finite monomer concentration, by implementing a new semi-analytical method, which involves computing the second virial coefficient, a thermodynamic indicator of inter-molecular interactions. This method, together with the symmetrized structure-based (Go) model, minimizes the need for expensive many-protein simulations, providing a convenient framework to investigate concentration effect. Finally, we perform direct simulations of domain-swapped trimer formation, showing that this modeling approach can be used for higher-order oligomers. (c) 2005 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Yang2005a,
author = {Yang, S. C. and Levine, H. and Onuchic, J. N.},
title = {Protein oligomerization through domain swapping: Role of inter-molecular interactions and protein concentration},
journal = {Journal Of Molecular Biology},
year = {2005},
volume = {352},
number = {1},
pages = {202--211}
}
|
| Yang, S.C., Levine, H., Onuchic, J.N. & Cox, D.L. (2005), "Structure of infectious prions: stabilization by domain swapping", Faseb Journal. Vol. 19(13), pp. 1778-1782.
[Abstract] [BibTeX]
|
| Abstract: A candidate structure for the minimal prion infectious unit is a recently discovered protein oligomer modeled as a beta-helical prion trimer (BPT); BPTs can stack to form cross-beta fibrils and may provide insight into protein aggregates of other amyloid diseases. However, the BPT lacks a clear intermonomer binding mechanism. Here we propose an alternative domain-swapped trimeric prion (DSTP) model and show with molecular dynamics (MD) that the DSTP has more favorable intermonomer hydrogen bonding and proline dihedral strain energy than the BPT. This new structural proposal may be tested by lysine and N terminus fluorescent resonance energy transfer (FRET) either directly on recombinant prion protein amyloid aggregates or on synthetic constructs that contain the proline/lysine-rich hinge region critical for domains to swap. In addition, the domain swapping may provide 1) intrinsic entanglement, which can contribute to the remarkable temperature stability of the infectious prion structure and help explain the absence of PrPSc monomers, 2) insight into why specific prolines are potentially relevant to three inherited forms of prion disease, and 3) a simple explanation of prion strains assuming the strain is encoded in the monomer number of the oligomers. |
BibTeX:
@article{Yang2005,
author = {Yang, S. C. and Levine, H. and Onuchic, J. N. and Cox, D. L.},
title = {Structure of infectious prions: stabilization by domain swapping},
journal = {Faseb Journal},
year = {2005},
volume = {19},
number = {13},
pages = {1778--1782}
}
|
| Chavez, L.L., Onuchic, J.N. & Clementi, C. (2004), "Quantifying the roughness on the free energy landscape: Entropic bottlenecks and protein folding rates", Journal Of The American Chemical Society. Vol. 126(27), pp. 8426-8432.
[Abstract] [BibTeX]
|
| Abstract: The prediction of protein folding rates and mechanisms is currently of great interest in the protein folding community. A close comparison between theory and experiment in this area is promising to advance our understanding of the physical-chemical principles governing the folding process. The delicate interplay of entropic and energetic/enthalpic factors in the protein free energy regulates the details of this complex reaction. In this article, we propose the use of topological descriptors to quantify the amount of heterogeneity in the configurational entropy contribution to the free energy. We apply the procedure to a set of 16 two-state folding proteins. The results offer a clean and simple theoretical explanation for the experimentally measured folding rates and mechanisms, in terms of the intrinsic entropic roughness along the populated folding routes on the protein free energy landscape. |
BibTeX:
@article{Chavez2004,
author = {Chavez, L. L. and Onuchic, J. N. and Clementi, C.},
title = {Quantifying the roughness on the free energy landscape: Entropic bottlenecks and protein folding rates},
journal = {Journal Of The American Chemical Society},
year = {2004},
volume = {126},
number = {27},
pages = {8426--8432}
}
|
| Cheung, M.S., Chavez, L.L. & Onuchic, J.N. (2004), "The energy landscape for protein folding and possible connections to function", Polymer. Vol. 45(2), pp. 547-555.
[Abstract] [BibTeX]
|
| Abstract: In this article we review and discuss the state-of-the-art methods using minimalist models in the context of energy landscape theory to study protein folding. As good agreement between computational/theoretical studies and experimental observations in vitro continues to emerge, many research groups are asking how this structural and dynamical information can be used to understand proteins in vivo. This is a non-trivial question drawing from very limited in vivo studies. From the perspective of theory, it is a new horizon for theoreticians to test or revise their theories by making connections to experiments on this matter. We present a short discussion of several recent efforts that include factors reflecting the cellular environment in computer simulations-and that may provide some insight into the behavior of protein dynamics inside the living cell as well as inspire the development of new experimental approaches for a better understanding of the molecular mechanisms for function. (C) 2003 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Cheung2004a,
author = {Cheung, M. S. and Chavez, L. L. and Onuchic, J. N.},
title = {The energy landscape for protein folding and possible connections to function},
journal = {Polymer},
year = {2004},
volume = {45},
number = {2},
pages = {547--555}
}
|
| Cheung, M.S. & Onuchic, J.N. (2004), "Solvation in protein folding analysis, combination of theoretical and experimental approaches.", Biophysical Journal. Vol. 86(1), pp. 344A-344A.
[BibTeX]
|
BibTeX:
@article{Cheung2004,
author = {Cheung, M. S. and Onuchic, J. N.},
title = {Solvation in protein folding analysis, combination of theoretical and experimental approaches.},
journal = {Biophysical Journal},
year = {2004},
volume = {86},
number = {1},
pages = {344A--344A}
}
|
| Fernandez-Escamilla, A.M., Cheung, M.S., Vega, M.C., Wilmanns, M., Onuchic, J.N. & Serrano, L. (2004), "Solvation in protein folding analysis: Combination of theoretical and experimental approaches", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 101(9), pp. 2834-2839.
[Abstract] [BibTeX]
|
| Abstract: An effort to combine theoretical analyses and protein engineering methods has been made to probe the folding mechanism of SH3 by using Energy Landscape Theory and a phi-value analysis. Particular emphasis was given to core residues and the effect of desolvation during the folding event by replacing the core valines with isosteric threonines. These mutations have the advantage of keeping the core structurally invariant while affecting core stability relative to the unfolded state. Although the valines that form the core appear spatially invariant, the folding kinetics of their threonine mutants varies, indicating their different extent of solvation in the transition-state ensemble. Theoretical studies predicted the distribution of folding kinetics of threonine mutants without previous knowledge of the measured rates. This initial success encourages further investigations of the molecular details behind these macroscopic phenomena and of the role of solvation in the folding mechanism. |
BibTeX:
@article{Fernandez-Escamilla2004,
author = {Fernandez-Escamilla, A. M. and Cheung, M. S. and Vega, M. C. and Wilmanns, M. and Onuchic, J. N. and Serrano, L.},
title = {Solvation in protein folding analysis: Combination of theoretical and experimental approaches},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2004},
volume = {101},
number = {9},
pages = {2834--2839}
}
|
| Finke, J.M., Cheung, M.S., Jennings, P.A., Smith, D.E. & Onuchic, J.N. (2004), "Simulations and experiments to study protein folding, aggregation, and polyglutamine disease", Protein Science. Vol. 13, pp. 171-171.
[BibTeX]
|
BibTeX:
@article{Finke2004d,
author = {Finke, J. M. and Cheung, M. S. and Jennings, P. A. and Smith, D. E. and Onuchic, J. N.},
title = {Simulations and experiments to study protein folding, aggregation, and polyglutamine disease},
journal = {Protein Science},
year = {2004},
volume = {13},
pages = {171--171}
}
|
| Finke, J.M., Cheung, M.S. & Onuchic, J.N. (2004), "A structural model of polyglutamine determined from a host-guest method combining experiments and landscape theory", Biophysical Journal. Vol. 87(3), pp. 1900-1918.
[Abstract] [BibTeX]
|
| Abstract: Modeling the structure of natively disordered peptides has proved difficult due to the lack of structural information on these peptides. In this work, we use a novel application of the host-guest method, combining folding theory with experiments, to model the structure of natively disordered polyglutamine peptides. Initially, a minimalist molecular model (CalphaCbeta) of CI2 is developed with a structurally based potential and captures many of the folding properties of CI2 determined from experiments. Next, polyglutamine "guest'' inserts of increasing length are introduced into the CI2 "host'' model and the polyglutamine is modeled to match the resultant change in CI2 thermodynamic stability between simulations and experiments. The polyglutamine model that best mimics the experimental changes in CI2 thermodynamic stability has 1), a beta-strand dihedral preference and 2), an attractive energy between polyglutamine atoms 0.75-times the attractive energy between the CI2 host Go-contacts. When free-energy differences in the CI2 host-guest system are correctly modeled at varying lengths of polyglutamine guest inserts, the kinetic folding rates and structural perturbation of these CI2 insert mutants are also correctly captured in simulations without any additional parameter adjustment. In agreement with experiments, the residues showing structural perturbation are located in the immediate vicinity of the loop insert. The simulated polyglutamine loop insert predominantly adopts extended random coil conformations, a structural model consistent with low resolution experimental methods. The agreement between simulation and experimental CI2 folding rates, CI2 structural perturbation, and polyglutamine insert structure show that this host-guest method can select a physically realistic model for inserted polyglutamine. If other amyloid peptides can be inserted into stable protein hosts and the stabilities of these host-guest mutants determined, this novel host-guest method may prove useful to determine structural preferences of these intractable but biologically relevant protein fragments. |
BibTeX:
@article{Finke2004b,
author = {Finke, J. M. and Cheung, M. S. and Onuchic, J. N.},
title = {A structural model of polyglutamine determined from a host-guest method combining experiments and landscape theory},
journal = {Biophysical Journal},
year = {2004},
volume = {87},
number = {3},
pages = {1900--1918}
}
|
| Finke, J.M., Matthews, C. & Onuchic, J.N. (2004), "Exploring TIM barrel folding with minimalist simulations and landscape theory", Protein Science. Vol. 13, pp. 224-224.
[BibTeX]
|
BibTeX:
@article{Finke2004c,
author = {Finke, J. M. and Matthews, C. and Onuchic, J. N.},
title = {Exploring TIM barrel folding with minimalist simulations and landscape theory},
journal = {Protein Science},
year = {2004},
volume = {13},
pages = {224--224}
}
|
| Finke, J.M. & Onuchic, J.N. (2004), "Minimalist simulations to study protein folding, aggregation, and polyglutamine disease.", Abstracts of Papers American Chemical Society. Vol. 227(Part 1), pp. U223.
[BibTeX]
|
BibTeX:
@article{Finke2004,
author = {Finke, John M. and Onuchic, Jose N.},
title = {Minimalist simulations to study protein folding, aggregation, and polyglutamine disease.},
journal = {Abstracts of Papers American Chemical Society},
year = {2004},
volume = {227},
number = {Part 1},
pages = {U223}
}
|
| Finke, J.M. & Onuchic, J.N. (2004), "Simulations exploring the structural ensemble in the folding of proteins and amyloid peptides", Biophysical Journal. Vol. 86(1), pp. 340A-340A.
[BibTeX]
|
BibTeX:
@article{Finke2004a,
author = {Finke, J. M. and Onuchic, J. N.},
title = {Simulations exploring the structural ensemble in the folding of proteins and amyloid peptides},
journal = {Biophysical Journal},
year = {2004},
volume = {86},
number = {1},
pages = {340A--340A}
}
|
| Garcia, A.E. & Onuchic, J.N. (2004), "All atom simulation of the folding/unfolding thermodynamics of protein A", Biophysical Journal. Vol. 86(1), pp. 345A-345A.
[BibTeX]
|
BibTeX:
@article{Garcia2004,
author = {Garcia, A. E. and Onuchic, J. N.},
title = {All atom simulation of the folding/unfolding thermodynamics of protein A},
journal = {Biophysical Journal},
year = {2004},
volume = {86},
number = {1},
pages = {345A--345A}
}
|
| Leite, V.B.P., Onuchic, J.N., Stell, G. & Wang, J. (2004), "Probing the kinetics of single molecule protein folding", Biophysical Journal. Vol. 87, pp. 3633-3641.
[Abstract] [BibTeX]
|
| Abstract: We propose an approach to integrate the theory, simulations, and experiments in protein-folding kinetics. This is realized by measuring the mean and high-order moments of the first-passage time and its associated distribution. The full kinetics is revealed in the current theoretical framework through these measurements. In the experiments, information about the statistical properties of first-passage times can be obtained from the kinetic folding trajectories of single molecule experiments ( for example, fluorescence). Theoretical/simulation and experimental approaches can be directly related. We study in particular the temperature-varying kinetics to probe the underlying structure of the folding energy landscape. At high temperatures, exponential kinetics is observed; there are multiple parallel kinetic paths leading to the native state. At intermediate temperatures, nonexponential kinetics appears, revealing the nature of the distribution of local traps on the landscape and, as a result, discrete kinetic paths emerge. At very low temperatures, exponential kinetics is again observed; the dynamics on the underlying landscape is dominated by a single barrier. The ratio between first-passage-time moments is proposed to be a good variable to quantitatively probe these kinetic changes. The temperature-dependent kinetics is consistent with the strange kinetics found in folding dynamics experiments. The potential applications of the current results to single-molecule protein folding are discussed. |
BibTeX:
@article{Leite2004,
author = {Leite, V. B. P. and Onuchic, J. N. and Stell, G. and Wang, J.},
title = {Probing the kinetics of single molecule protein folding},
journal = {Biophysical Journal},
year = {2004},
volume = {87},
pages = {3633--3641}
}
|
| Levy, Y., Caflisch, A., Onuchic, J.N. & Wolynes, P.G. (2004), "The folding and dimerization of HIV-1 protease: Evidence for a stable monomer from simulations", Journal Of Molecular Biology. Vol. 340(1), pp. 67-79.
[Abstract] [BibTeX]
|
| Abstract: HIV-1 protease (PR) is a major drug target in combating AIDS, as it plays a key role in maturation and replication of the virus. Six FDA-approved drugs are currently in clinical use, all designed to inhibit enzyme activity by blocking the active site, which exists only in the dimer. An alternative inhibition mode would be required to overcome the emergence of drug-resistance through the accumulation of mutations. This might involve ' inhibiting the formation of the dimer itself. Here, the folding of HIV-1 PR dimer is studied with several simulation models appropriate for folding mechanism studies. Simulations with an off-lattice Go-model, which corresponds to a perfectly funneled energy landscape, indicate that the enzyme is formed by association of structured monomers. All-atom molecular dynamics simulations strongly support the stability of an isolated monomer. The conjunction of results from a model that focuses on the protein topology and a detailed all-atom force-field model suggests, in contradiction to some reported equilibrium denaturation experiments, that monomer folding and dimerization are decoupled. The simulation result is, however, in agreement with the recent NMR detection of folded monomers of HIV-1 PR mutants with a destabilized interface. Accordingly, the design of dimerization inhibitors should not focus only on the flexible N and C termini that constitute most of the dimer interface, but also on other structured regions of the monomer. In particular, the relatively high phi values for residues 23-35 and 79-87 in both the folding and binding transition states, together with their proximity to the interface, highlight them as good targets for inhibitor design. (C) 2004 Elsevier Ltd. All rights reserved. |
BibTeX:
@article{Levy2004c,
author = {Levy, Y. and Caflisch, A. and Onuchic, J. N. and Wolynes, P. G.},
title = {The folding and dimerization of HIV-1 protease: Evidence for a stable monomer from simulations},
journal = {Journal Of Molecular Biology},
year = {2004},
volume = {340},
number = {1},
pages = {67--79}
}
|
| Levy, Y. & Onuchic, J.N. (2004), "Water and proteins: A love-hate relationship", Proceedings Of The National Academy Of Sciences Of The United States Of America. Vol. 101(10), pp. 3325-3326.
[BibTeX]
|
BibTeX:
@article{Levy2004,
author = {Levy, Y. and Onuchic, J. N.},
title = {Water and proteins: A love-hate relationship},
journal = {Proceedings Of The National Academy Of Sciences Of The United States Of America},
year = {2004},
volume = {101},
number = {10},
pages = {3325--3326}
}
|
| Levy, Y., Papoian, G.A., Onuchic, J.N. & Wolynes, P.G. (2004), "Energy landscape analysis of protein dimers", Israel Journal Of Chemistry. Vol. 44(1-3), pp. 281-297.
[Abstract] [BibTeX]
|
| Abstract: Many cellular functions are carried out by proteins that are bound together in multiprotein complexes. The binding between two highly flexible proteins to form homodimers is studied here using energy landscape theory and simulations based on a perfectly funneled energy landscape. With the aim to survey the range of binding mechanisms, two sets of homodimers were selected based on the experimental knowledge of whether stable monomers are needed for binding to take place. We find that the binding mechanism can be predicted based on the structure of the complex subunits alone. On average, the theory predicts a lower stability for subunits that are less compact and less hydrophobic, indicating, in agreement with their experimental classification, that their folding will be coupled to their binding. On the other hand, when a monomeric intermediate is experi |