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.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$736,822
Indirect Cost
City
State
Country
Zip Code
Sirur, Anshul; De Sancho, David; Best, Robert B (2016) Markov state models of protein misfolding. J Chem Phys 144:075101
Kührová, Petra; Best, Robert B; Bottaro, Sandro et al. (2016) Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies. J Chem Theory Comput 12:4534-48
Best, Robert B; Hummer, Gerhard (2016) Microscopic interpretation of folding Ï•-values using the transition path ensemble. Proc Natl Acad Sci U S A 113:3263-8
Borgia, Alessandro; Zheng, Wenwei; Buholzer, Karin et al. (2016) Consistent View of Polypeptide Chain Expansion in Chemical Denaturants from Multiple Experimental Methods. J Am Chem Soc 138:11714-26
Zheng, Wenwei; de Sancho, David; Best, Robert B (2016) Modulation of Folding Internal Friction by Local and Global Barrier Heights. J Phys Chem Lett 7:1028-34
Zheng, Wenwei; Borgia, Alessandro; Buholzer, Karin et al. (2016) Probing the Action of Chemical Denaturant on an Intrinsically Disordered Protein by Simulation and Experiment. J Am Chem Soc 138:11702-13
Zerze, Gül H; Mittal, Jeetain; Best, Robert B (2016) Diffusive Dynamics of Contact Formation in Disordered Polypeptides. Phys Rev Lett 116:068102
Tian, Pengfei; Best, Robert B (2016) Structural Determinants of Misfolding in Multidomain Proteins. PLoS Comput Biol 12:e1004933
Best, Robert B; Hofmann, Hagen; Nettels, Daniel et al. (2015) Quantitative interpretation of FRET experiments via molecular simulation: force field and validation. Biophys J 108:2721-31
Zheng, Wenwei; De Sancho, David; Hoppe, Travis et al. (2015) Dependence of internal friction on folding mechanism. J Am Chem Soc 137:3283-90

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