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A. H. Ratje; J. Loerke; A. Mikolajka; M. Brunner; P. W. Hildebrand; A. L. Starosta; A. Donhofer; S. R. Connell; P. Fucini; T. Mielke; P. C. Whitford; J. N. Onuchic; Y. N. Yu; K. Y. Sanbonmatsu; R. K. Hartmann; P. A. Penczek; D. N. Wilson & C. M. T. Spahn. Head swivel on the ribosome facilitates translocation by means of intra-subunit tRNA hybrid sites. Nature, Volume 468, Number 7324, Pages 713-U143, 2010. [Abstract] [BibTeX] [DOI]
Abstract: The elongation cycle of protein synthesis involves the delivery of aminoacyl-transfer RNAs to the aminoacyl-tRNA-binding site (A site) of the ribosome, followed by peptide-bond formation and translocation of the tRNAs through the ribosome to reopen the A site(1,2). The translocation reaction is catalysed by elongation factor G (EF-G) in a GTP-dependent manner(3). Despite the availability of structures of various EF-G-ribosome complexes, the precise mechanism by which tRNAs move through the ribosome still remains unclear. Here we use multiparticle cryoelectron microscopy analysis to resolve two previously unseen subpopulations within Thermus thermophilus EF-G-ribosome complexes at subnanometre resolution, one of them with a partly translocated tRNA. Comparison of these substates reveals that translocation of tRNA on the 30S subunit parallels the swivelling of the 30S head and is coupled to unratcheting of the 30S body. Because the tRNA maintains contact with the peptidyl-tRNA-binding site (P site) on the 30S head and simultaneously establishes interaction with the exit site (E site) on the 30S platform, a novel intra-subunit 'pe/E' hybrid state is formed. This state is stabilized by domain IV of EF-G, which interacts with the swivelled 30S-head conformation. These findings provide direct structural and mechanistic insight into the 'missing link' in terms of tRNA intermediates involved in the universally conserved translocation process.
BibTeX: @article{,
author = {Ratje, A. H. and Loerke, J. and Mikolajka, A. and Brunner, M. and Hildebrand, P. W. and Starosta, A. L. and Donhofer, A. and Connell, S. R. and Fucini, P. and Mielke, T. and Whitford, P. C. and Onuchic, J. N. and Yu, Y. N. and Sanbonmatsu, K. Y. and Hartmann, R. K. and Penczek, P. A. and Wilson, D. N. and Spahn, C. M. T.},
title = {Head swivel on the ribosome facilitates translocation by means of intra-subunit tRNA hybrid sites},
journal = {Nature},
year = {2010},
volume = {468},
number = {7324},
pages = {713--U143},
doi = {10.1038/nature09547}
}
A. Schug & J. N. Onuchic. From protein folding to protein function and biomolecular binding by energy landscape theory. Current Opinion In Pharmacology, Volume 10, Number 6, Pages 709-714, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Protein folding and function are inherently linked sharing a joined funneled energy landscape In this theoretical framework, the integration of simulations, structural information, and sequence data has led to quantitatively explore, understand and predict biomolecular binding and recognition key processes in pharmacology, as a natural extension of the selective self-binding found in protein folding Computer simulations based on these principles have made valuable contributions to understanding protein and RNA folding protein-protein interactions, and protein-metabolite/RNA-metabolite interactions
BibTeX: @article{,
author = {Schug, A. and Onuchic, J. N.},
title = {From protein folding to protein function and biomolecular binding by energy landscape theory},
journal = {Current Opinion In Pharmacology},
year = {2010},
volume = {10},
number = {6},
pages = {709--714},
doi = {10.1016/j.coph.2010.09.012}
}
M. A. Jamros; L. C. Oliveira; P. C. Whitford; J. N. Onuchic; J. A. Adams; D. K. Blumenthal & P. A. Jennings. Proteins at Work A COMBINED SMALL ANGLE X-RAY SCATTERING AND THEORETICAL DETERMINATION OF THE MULTIPLE STRUCTURES INVOLVED ON THE PROTEIN KINASE FUNCTIONAL LANDSCAPE. Journal of Biological Chemistry, Volume 285, Number 46, Pages 36121-36128, 2010. [Abstract] [BibTeX] [DOI]
Abstract: C-terminal Src kinase (Csk) phosphorylates and down-regulates the Src family tyrosine kinases (SFKs). Crystallographic studies of Csk found an unusual arrangement of the SH2 and SH3 regulatory domains about the kinase core, forming a compact structure. However, recent structural studies of mutant Csk in the presence of an inhibitor indicate that the enzyme accesses an expanded structure. To investigate whether wt-Csk may also access open conformations we applied small angle x-ray scattering (SAXS). We find wt-Csk frequently occupies an extended conformation where the regulatory domains are removed from the kinase core. In addition, all-atom structure-based simulations indicate Csk occupies two free energy basins. These basins correspond to ensembles of distinct global conformations of Csk: a compact structure and an extended structure. The transitions between these structures are entropically driven and accessible via thermal fluctuations that break local interactions. We further characterized the ensemble by generating theoretical scattering curves for mixed populations of conformations from both basins and compared the predicted scattering curves to the experimental profile. This population-combination analysis is more consistent with the experimental data than any rigid model. It suggests that Csk adopts a broad ensemble of conformations in solution, populating extended conformations not observed in the crystal structure that may play an important role in the regulation of Csk. The methodology developed here is broadly applicable to biological macromolecules and will provide useful information about what ensembles of conformations are consistent with the experimental data as well as the ubiquitous dynamic reversible assembly processes inherent in biology.
BibTeX: @article{,
author = {Jamros, M. A. and Oliveira, L. C. and Whitford, P. C. and Onuchic, J. N. and Adams, J. A. and Blumenthal, D. K. and Jennings, P. A.},
title = {Proteins at Work A COMBINED SMALL ANGLE X-RAY SCATTERING AND THEORETICAL DETERMINATION OF THE MULTIPLE STRUCTURES INVOLVED ON THE PROTEIN KINASE FUNCTIONAL LANDSCAPE},
journal = {Journal of Biological Chemistry},
year = {2010},
volume = {285},
number = {46},
pages = {36121--36128},
doi = {10.1074/jbc.M110.116947}
}
P. C. Whitford; J. N. Onuchic & K. Y. Sanbonmatsu. Connecting Energy Landscapes with Experimental Rates for Aminoacyl-tRNA Accommodation in the Ribosome. Journal of the American Chemical Society, Volume 132, Number 38, Pages 13170-13171, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Using explicit-solvent simulations of the 70S ribosome, the barrier-crossing attempt frequency was calculated for aminoacyl-tRNA elbow-accommodation. In seven individual trajectories (200-300 ns, each, for an aggregate time of 2.1 mu s), the relaxation time of tRNA structural fluctuations was determined to be similar to 10 ns, and the barrier-crossing attempt frequency of tRNA accommodation is similar to 1-10 mu s(-1). These calculations provide a quantitative relationship between the free-energy barrier and experimentally measured rates of accommodation, which demonstrate that the free-energy barrier of elbow-accommodation is less than 15 k(B) T, in vitro and in vivo.
BibTeX: @article{,
author = {Whitford, P. C. and Onuchic, J. N. and Sanbonmatsu, K. Y.},
title = {Connecting Energy Landscapes with Experimental Rates for Aminoacyl-tRNA Accommodation in the Ribosome},
journal = {Journal of the American Chemical Society},
year = {2010},
volume = {132},
number = {38},
pages = {13170--13171},
doi = {10.1021/ja1061399}
}
J. K. Noel; J. I. Sulkowska & J. N. Onuchic. Slipknotting upon native-like loop formation in a trefoil knot protein. Proceedings of the National Academy of Sciences of the United States of America, Volume 107, Number 35, Pages 15403-15408, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate.
BibTeX: @article{,
author = {Noel, J. K. and Sulkowska, J. I. and Onuchic, J. N.},
title = {Slipknotting upon native-like loop formation in a trefoil knot protein},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2010},
volume = {107},
number = {35},
pages = {15403--15408},
doi = {10.1073/pnas.1009522107}
}
R. J. Oliveira; P. C. Whitford; J. Chahine; J. Wang; J. N. Onuchic & V. B. P. Leite. The Origin of Nonmonotonic Complex Behavior and the Effects of Nonnative Interactions on the Diffusive Properties of Protein Folding. Biophysical Journal, Volume 99, Number 2, Pages 600-608, 2010. [Abstract] [BibTeX] [DOI]
Abstract: We present a method for calculating the configurational-dependent diffusion coefficient of a globular protein as a function of the global folding process. Using a coarse-grained structure-based model, we determined the diffusion coefficient, in reaction coordinate space, as a function of the fraction of native contacts formed Q for the cold shock protein (TmCSP). We find nonmonotonic behavior for the diffusion coefficient, with high values for the folded and unfolded ensembles and a lower range of values in the transition state ensemble. We also characterized the folding landscape associated with an energetically frustrated variant of the model. We find that a low-level of frustration can actually stabilize the native ensemble and increase the associated diffusion coefficient. These findings can be understood from a mechanistic standpoint, in that the transition state ensemble has a more homogeneous structural content when frustration is present. Additionally, these findings are consistent with earlier calculations based on lattice models of protein folding and more recent single-molecule fluorescence measurements.
BibTeX: @article{,
author = {Oliveira, R. J. and Whitford, P. C. and Chahine, J. and Wang, J. and Onuchic, J. N. and Leite, V. B. P.},
title = {The Origin of Nonmonotonic Complex Behavior and the Effects of Nonnative Interactions on the Diffusive Properties of Protein Folding},
journal = {Biophysical Journal},
year = {2010},
volume = {99},
number = {2},
pages = {600--608},
doi = {10.1016/j.bpj.2010.04.041}
}
J. K. Noel; P. C. Whitford; K. Y. Sanbonmatsu & J. N. Onuchic. SMOG@ctbp: simplified deployment of structure-based models in GROMACS. Nucleic Acids Research, Volume 38, Pages W657-W661, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Molecular dynamics simulations with coarse-grained and/or simplified Hamiltonians are an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Structure-based Hamiltonians, simplified models developed from the energy landscape theory of protein folding, have become a standard tool for investigating biomolecular dynamics. SMOG@ctbp is an effort to simplify the use of structure-based models. The purpose of the web server is two fold. First, the web tool simplifies the process of implementing a well-characterized structure-based model on a state-of-the-art, open source, molecular dynamics package, GROMACS. Second, the tutorial-like format helps speed the learning curve of those unfamiliar with molecular dynamics. A web tool user is able to upload any multi-chain biomolecular system consisting of standard RNA, DNA and amino acids in PDB format and receive as output all files necessary to implement the model in GROMACS. Both C-alpha and all-atom versions of the model are available. SMOG@ctbp resides at http://smog-server.org.
BibTeX: @article{,
author = {Noel, J. K. and Whitford, P. C. and Sanbonmatsu, K. Y. and Onuchic, J. N.},
title = {SMOG@ctbp: simplified deployment of structure-based models in GROMACS},
journal = {Nucleic Acids Research},
year = {2010},
volume = {38},
pages = {W657--W661},
doi = {10.1093/nar/gkq498}
}
D. Bolinger; J. I. Sulkowska; H. P. Hsu; L. A. Mirny; M. Kardar; J. N. Onuchic & P. Virnau. A Stevedore's Protein Knot. Plos Computational Biology, Volume 6, Number 4, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Protein knots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Seven distinctly knotted folds have already been identified. It is by and large unclear how these exceptional structures actually fold, and only recently, experiments and simulations have begun to shed some light on this issue. In checking the new protein structures submitted to the Protein Data Bank, we encountered the most complex and the smallest knots to date: A recently uncovered alpha-haloacid dehalogenase structure contains a knot with six crossings, a so-called Stevedore knot, in a projection onto a plane. The smallest protein knot is present in an as yet unclassified protein fragment that consists of only 92 amino acids. The topological complexity of the Stevedore knot presents a puzzle as to how it could possibly fold. To unravel this enigma, we performed folding simulations with a structure-based coarse-grained model and uncovered a possible mechanism by which the knot forms in a single loop flip.
BibTeX: @article{,
author = {Bolinger, D. and Sulkowska, J. I. and Hsu, H. P. and Mirny, L. A. and Kardar, M. and Onuchic, J. N. and Virnau, P.},
title = {A Stevedore's Protein Knot},
journal = {Plos Computational Biology},
year = {2010},
volume = {6},
number = {4},
doi = {10.1371/journal.pcbi.1000731}
}
P. C. Whitford; P. Geggier; R. B. Altman; S. C. Blanchard; J. N. Onuchic & K. Y. Sanbonmatsu. Accommodation of aminoacyl-tRNA into the ribosome involves reversible excursions along multiple pathways. Rna-a Publication of the Rna Society, Volume 16, Number 6, Pages 1196-1204, 2010. [Abstract] [BibTeX] [DOI]
Abstract: The ribosome is a massive ribonucleoprotein complex (similar to 2.4 MDa) that utilizes large-scale structural fluctuations to produce unidirectional protein synthesis. Accommodation is a key conformational change during transfer RNA (tRNA) selection that allows movement of tRNA into the ribosome. Here, we address the structure-function relationship that governs accommodation using all-atom molecular simulations and single-molecule fluorescence resonance energy transfer (smFRET). Simulations that employ an all-atom, structure-based (G (o) over bar -like) model illuminate the interplay between configurational entropy and effective enthalpy during the accommodation process. This delicate balance leads to spontaneous reversible accommodation attempts, which are corroborated by smFRET measurements. The dynamics about the endpoints of accommodation (the A/T and A/A conformations) obtained from structure-based simulations are validated by multiple 100-200 ns explicit-solvent simulations (3.2 million atoms for a cumulative 1.4 mu s), and previous crystallographic analysis. We find that the configurational entropy of the 3'-CCA end of aminoacyl-tRNA resists accommodation, leading to a multistep accommodation process that encompasses a distribution of parallel pathways. The calculated mechanism is robust across simulation methods and protocols, suggesting that the structure of the accommodation corridor imposes stringent limitations on the accessible pathways. The identified mechanism and observed parallel pathways establish an atomistic framework for interpreting a large body of biochemical data and demonstrate that conformational changes during translation occur through a stochastic trial-and-error process, rather than in concerted lock-step motions.
BibTeX: @article{,
author = {Whitford, P. C. and Geggier, P. and Altman, R. B. and Blanchard, S. C. and Onuchic, J. N. and Sanbonmatsu, K. Y.},
title = {Accommodation of aminoacyl-tRNA into the ribosome involves reversible excursions along multiple pathways},
journal = {Rna-a Publication of the Rna Society},
year = {2010},
volume = {16},
number = {6},
pages = {1196--1204},
doi = {10.1261/rna.2035410}
}
A. Schug; M. Weigt; J. A. Hoch; J. N. Onuchic; T. Hwa & H. Szurmant. Computational Modeling of Phosphotransfer Complexes In Two-component Signaling. Methods In Enzymology, Vol 471: Two-component Signaling Systems, Part C, Volume 471, Pages 43-58, 2010. [Abstract] [BibTeX] [DOI]
Abstract: Two-component signal transduction systems enable cells in bacteria, fungi, and plants to react to extracellular stimuli. A sensor histidine kinase (SK) detects such stimuli with its sensor domains and transduces the input signals to a response regulator (RR) by trans-phosphorylation. This trans-phosphorylation reaction requires the formation of a complex formed by the two interacting proteins. The complex is stabilized by transient interactions. The nature of the transient interactions makes it challenging for experimental techniques to gain structural information. X-ray crystallography requires stable crystals, which are difficult to grow and stabilize. Similarly, the mere size of these systems proves problematic for NMR. Theoretical methods can, however, complement existing data. The statistical direct coupling analysis presented in the previous chapter reveals the interacting residues at the contact interface of the SK/RR pair. This information can be combined with the structures of the individual proteins in molecular dynamical simulation to generate structural models of the complex. The general approach, referred to as MAGMA, was tested on the sporulation phosphorelay phosphotransfer complex, the Spo0B/Spo0F pair, delivering crystal resolution accuracy. The MAGMA method is described here in a step-by-step explanation. The developed parameters are transferrable to other SK/RR systems.
BibTeX: @article{,
author = {Schug, A. and Weigt, M. and Hoch, J. A. and Onuchic, J. N. and Hwa, T. and Szurmant, H.},
title = {Computational Modeling of Phosphotransfer Complexes In Two-component Signaling},
journal = {Methods In Enzymology, Vol 471: Two-component Signaling Systems, Part C},
year = {2010},
volume = {471},
pages = {43--58},
doi = {10.1016/S0076-6879(10)71003-X}
}
A. Schug; M. Weigt; J. N. Onuchic; T. Hwa & H. Szurmant. High-resolution protein complexes from integrating genomic information with molecular simulation. Proceedings of the National Academy of Sciences of the United States of America, Volume 106, Number 52, Pages 22124-22129, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Bacteria use two-component signal transduction systems (TCS) extensively to sense and react to external stimuli. In these, a membrane-bound sensor histidine kinase (SK) autophosphorylates in response to an environmental stimulus and transfers the phosphoryl group to a transcription factor/response regulator (RR) that mediates the cellular response. The complex between these two proteins is ruled by transient interactions, which provides a challenge to experimental structure determination techniques. The functional and structural homolog of an SK/RR pair Spo0B/Spo0F, however, has been structurally resolved. Here, we describe a method capable of generating structural models of such transient protein complexes. By using existing structures of the individual proteins, our method combines bioinformatically derived contact residue information with molecular dynamics simulations. We find crystal resolution accuracy with existing crystallographic data when reconstituting the known system Spo0B/Spo0F. Using this approach, we introduce a complex structure of TM0853/TM0468 as an exemplary SK/RR TCS, consistent with all experimentally available data.
BibTeX: @article{,
author = {Schug, A. and Weigt, M. and Onuchic, J. N. and Hwa, T. and Szurmant, H.},
title = {High-resolution protein complexes from integrating genomic information with molecular simulation},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2009},
volume = {106},
number = {52},
pages = {22124--22129},
doi = {10.1073/pnas.0912100106}
}
J. I. Sulkowska; P. Sulkowski & J. N. Onuchic. Jamming Proteins with Slipknots and Their Free Energy Landscape. Physical Review Letters, Volume 103, Number 26, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Theoretical studies of stretching proteins with slipknots reveal a surprising growth of their unfolding times when the stretching force crosses an intermediate threshold. This behavior arises as a consequence of the existence of alternative unfolding routes that are dominant at different force ranges. The existence of an intermediate, metastable configuration where the slipknot is jammed is responsible for longer unfolding times at higher forces. Simulations are performed with a coarse-grained model with further quantification using a refined description of the geometry of the slipknots. The simulation data are used to determine the free energy landscape of the protein, which supports recent analytical predictions.
BibTeX: @article{,
author = {Sulkowska, J. I. and Sulkowski, P. and Onuchic, J. N.},
title = {Jamming Proteins with Slipknots and Their Free Energy Landscape},
journal = {Physical Review Letters},
year = {2009},
volume = {103},
number = {26},
doi = {10.1103/PhysRevLett.103.268103}
}
D. Schultz; P. G. Wolynes; E. Ben Jacob & J. N. Onuchic. Deciding fate in adverse times: Sporulation and competence in Bacillus subtilis. Proceedings of the National Academy of Sciences of the United States of America, Volume 106, Number 50, Pages 21027-21034, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Bacteria serve as the central arena for understanding how gene networks and proteins process information and control cellular behaviors. Recently, much effort has been devoted to the investigation of specific bacteria gene circuits as functioning modules. The next challenge is the integrative modeling of complex cellular networks composed of many such modules. A tractable integrative model of the sophisticated decision-making signal transduction system that determines the fate between sporulation and competence is presented. This model provides an understanding of how information is sensed and processed to reach an "informative'' decision in the context of cell state and signals from other cells. The competence module (ComK dynamics) is modeled as a stochastic switch whose transition rate is controlled by a quorum-sensing unit. The sporulation module (Spo0A dynamics) is modeled as a timer whose clock rate is adjusted by a stress-sensing unit. The interplay between these modules is mediated via the Rap assessment system, which gates the sensing units, and the AbrB-Rok decision module, which creates an opportunity for competence within a specific window of the sporulation timer. The timer is regulated via a special repressilator-like inhibition of Spo0A* by Spo0E, which is itself inhibited by AbrB. For some stress and input signals, this repressilator can generate a frustration state with large variations (fluctuations or oscillations) in Spo0A* and AbrB concentrations, which might serve an important role in generating cell variability. This integrative framework is a starting point that can be extended to include transition into cannibalism and the role of colony organization.
BibTeX: @article{,
author = {Schultz, D. and Wolynes, P. G. and Ben Jacob, E. and Onuchic, J. N.},
title = {Deciding fate in adverse times: Sporulation and competence in Bacillus subtilis},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2009},
volume = {106},
number = {50},
pages = {21027--21034},
doi = {10.1073/pnas.0912185106}
}
A. F. P. de Araujo & J. N. Onuchic. A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins. Proceedings of the National Academy of Sciences of the United States of America, Volume 106, Number 45, Pages 19001-19004, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Protein tertiary structures are known to be encoded in amino acid sequences, but the problem of structure prediction from sequence continues to be a challenge. With this question in mind, recent simulations have shown that atomic burials, as expressed by atom distances to the molecular geometrical center, are sufficiently informative for determining native conformations of small globular proteins. Here we use a simple computational experiment to estimate the amount of this required burial information and find it to be surprisingly small, actually comparable with the stringent limit imposed by sequence statistics. Atomic burials appear to satisfy, therefore, minimal requirements for a putative dominating property in the folding code because they provide an amount of information sufficiently large for structural determination but, at the same time, sufficiently small to be encodable in sequences. In a simple analogy with human communication, atomic burials could correspond to the actual "language" encoded in the amino acid "script" from which the complexity of native conformations is recovered during the folding process.
BibTeX: @article{,
author = {de Araujo, A. F. P. and Onuchic, J. N.},
title = {A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2009},
volume = {106},
number = {45},
pages = {19001--19004},
doi = {10.1073/pnas.0910851106}
}
H. Lammert; A. Schug & J. N. Onuchic. Robustness and generalization of structure-based models for protein folding and function. Proteins-structure Function and Bioinformatics, Volume 77, Number 4, Pages 881-891, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Functional dynamics of native proteins share the energy landscape that guides folding into the native state. Folding simulations of structure-based protein models, using an minimally frustrated energy landscape dominated by native interactions, can describe the geometrical aspects of the folding mechanism. Technical limitations imposed by the fixed shape of conventional contact potentials are a key obstacle toward advanced applications of structure-based models like allostery or ligand binding, which require multiple stable conformations. Generalizations of existing models, commonly using Lennard-Jones-like potentials, lead to inevitable clashes between their repulsive branches, To resolve these challenges, a new contact potential is developed that combines an attractive part based on Gaussians with a separate repulsive term allowing flexibility for adjustments of the potential shape. With this new model multiple minima for studies of functional transitions can be introduced easily and consistently. A sensitivity analysis for five small proteins confirms the robust behavior of structure-based models with our adaptable potential and explores their capacity for quantitative adjustment of the folding thermodynamics. We demonstrate its ability to incorporate alternative contact distances in simulations of structural transitions for the well-studied ROP dimer. Individual contact pairs can switch between distinct sates to match the competing syn and anti structures. The flexibility of the new potential facilitates advanced uses of structure-based models. Deper ding on the application, features can be chosen from physical considerations or to match experiments. Generalized models can be built from multiple structures to study structural transitions or effects of disorder. Proteins 20:0; 77:881-891, (C) Wiley-Liss, Inc.
BibTeX: @article{,
author = {Lammert, H. and Schug, A. and Onuchic, J. N.},
title = {Robustness and generalization of structure-based models for protein folding and function},
journal = {Proteins-structure Function and Bioinformatics},
year = {2009},
volume = {77},
number = {4},
pages = {881--891},
doi = {10.1002/prot.22511}
}
Y. Gambin; A. Schug; E. A. Lemke; J. J. Lavinder; A. C. M. Ferreon; T. J. Magliery; J. N. Onuchic & A. A. Deniz. Direct single-molecule observation of a protein living in two opposed native structures. Proceedings of the National Academy of Sciences of the United States of America, Volume 106, Number 25, Pages 10153-10158, 2009. [Abstract] [BibTeX] [DOI]
Abstract: Biological activity in proteins requires them to share the energy landscape for folding and global conformational motions, 2 key determinants of function. Although most structural studies to date have focused on fluctuations around a single structural basin, we directly observe the coexistence of 2 symmetrically opposed conformations for a mutant of the Rop-homodimer ( Repressor of Primer) in single-molecule fluorescence resonance energy transfer (smFRET) measurements. We find that mild denaturing conditions can affect the sensitive balance between the conformations, generating an equilibrium ensemble consisting of 2 equally occupied structural basins. Despite the need for large-scale conformational rearrangement, both native structures are dynamically and reversibly adopted for the same paired molecules without separation of the constituent monomers. Such an ability of some proteins or protein complexes to switch between conformations by thermal fluctuations and/or minor environmental changes could be central to their ability to control biological function.
BibTeX: @article{,
author = {Gambin, Y. and Schug, A. and Lemke, E. A. and Lavinder, J. J. and Ferreon, A. C. M. and Magliery, T. J. and Onuchic, J. N. and Deniz, A. A.},
title = {Direct single-molecule observation of a protein living in two opposed native structures},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2009},
volume = {106},
number = {25},
pages = {10153--10158},
doi = {10.1073/pnas.0904461106}
}
C. Hyeon; S. Klumpp & J. N. Onuchic. Kinesin's backsteps under mechanical load. Physical Chemistry Chemical Physics, Volume 11, Number 24, Pages 4899-4910, 2009. [Abstract] [BibTeX] [DOI]
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