In the past year, this project has addressed several problems and methodological challenges in protein folding, most significantly: 1. Methodology for protein folding simulations. A description of protein folding or misfolding using atomistic simulations relies on the quality of the simulation model. Despite recent successes in ab initio folding simulations, there are still outstanding problems with the simulation models. These have been addressed here at a number of levels. At the most detailed, we have contributed to the development of the next generation of polarizable energy functions, which in principle should provide the most accurate description of the protein energy landscape (12). We have also worked to develop simpler, but more inexpensive computationally methods: firstly, by parametrizing non-polarizable models to match polarizable ones (2) and secondly, by developing models in which the solvent does not need to be explicitly modelled (7). These advances should ultimately result in a more reliable description of protein dynamics and function. 2. Protein folding mechanism. We have used molecular simulation models to test current protein folding theory. This has included a direct test of some key assumptions of the theory against a set of detailed atomistic simulations of nine different proteins in explicit water. We have found that the assumptions of the theory hold for naturally occurring proteins, the only exceptions being for simplified, designed proteins (6). We have further tested the theory against experimental data, by using the assumptions of the theory in simulations to predict the folding mechanism of spectrin domains (5). These results help to justify the use of simplified molecular models to provide insight into protein folding and function (10). 3. Role of molecular chaperonins in protein folding. We have used simulation and theory in order to analyze the effect of passive confinement inside chaperonins such as GroEL on protein folding. We have been able to explain experimental observations on folding rates inside chaperonins, and to propose a specific mechanism by which chaperonins can prevent misfolding in multidomain proteins.

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Kubas, Adam; De Sancho, David; Best, Robert B et al. (2014) Aerobic damage to [FeFe]-hydrogenases: activation barriers for the chemical attachment of O2. Angew Chem Int Ed Engl 53:4081-4
Knott, Michael; Best, Robert B (2014) Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model. J Chem Phys 140:175102
de Sancho, David; Sirur, Anshul; Best, Robert B (2014) Molecular origins of internal friction effects on protein-folding rates. Nat Commun 5:4307
Sirur, Anshul; Knott, Michael; Best, Robert B (2014) Effect of interactions with the chaperonin cavity on protein folding and misfolding. Phys Chem Chem Phys 16:6358-66
Wuttke, Rene; Hofmann, Hagen; Nettels, Daniel et al. (2014) Temperature-dependent solvation modulates the dimensions of disordered proteins. Proc Natl Acad Sci U S A 111:5213-8
Sirur, Anshul; Best, Robert B (2013) Effects of interactions with the GroEL cavity on protein folding rates. Biophys J 104:1098-106
Carter, James W; Baker, Christopher M; Best, Robert B et al. (2013) Engineering Folding Dynamics from Two-State to Downhill: Application to ýý-Repressor. J Phys Chem B 117:13435-43
Baker, Christopher M; Best, Robert B (2013) Matching of additive and polarizable force fields for multiscale condensed phase simulations. J Chem Theory Comput 9:2826-2837
Henry, Eric R; Best, Robert B; Eaton, William A (2013) Comparing a simple theoretical model for protein folding with all-atom molecular dynamics simulations. Proc Natl Acad Sci U S A 110:17880-5
Shi, Yue; Xia, Zhen; Zhang, Jiajing et al. (2013) The Polarizable Atomic Multipole-based AMOEBA Force Field for Proteins. J Chem Theory Comput 9:4046-4063

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