Constructing the equilibrium ensemble of folding pathways from short off-equilibrium simulations

作者：Frank Noé, Christof Schütte, Eric Vanden‐Eijnden, Lothar “Luther” Reich, Thomas R. Weikl · 发表于：Proceedings of the National Academy of Sciences · 年份：2009 · DOI：10.1073/pnas.0905466106 · 被引用次数：863 · 研究领域：Protein Structure and Dynamics、Mass Spectrometry Techniques and Applications、Spectroscopy and Quantum Chemical Studies

Characterizing the equilibrium ensemble of folding pathways, including their relative probability, is one of the major challenges in protein folding theory today. Although this information is in principle accessible via all-atom molecular dynamics simulations, it is difficult to compute in practice because protein folding is a rare event and the affordable simulation length is typically not sufficient to observe an appreciable number of folding events, unless very simplified protein models are used. Here we present an approach that allows for the reconstruction of the full ensemble of folding pathways from simulations that are much shorter than the folding time. This approach can be applied to all-atom protein simulations in explicit solvent. It does not use a predefined reaction coordinate but is based on partitioning the state space into small conformational states and constructing a Markov model between them. A theory is presented that allows for the extraction of the full ensemble of transition pathways from the unfolded to the folded configurations. The approach is applied to the folding of a PinWW domain in explicit solvent where the folding time is two orders of magnitude larger than the length of individual simulations. The results are in good agreement with kinetic experimental data and give detailed insights about the nature of the folding process which is shown to be surprisingly complex and parallel. The analysis reveals the existence of misfolded trap states outs...