Automated computation of low‐energy pathways for complex rearrangements in proteins: Application to the conformational switch of Ras p21

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Abstract
The computation of minimum energy paths (MEPs) is an approach for gaining insight into protein conformational transitions that are too slow to be observed with unconstrained molecular dynamics simulations. MEPs have the advantage of providing the energy barrier of the rate‐limiting step(s), allowing discrimination among different paths. Finding low‐energy MEPs for complex transitions, such as those involving rearrangements of the backbone fold or repacking of buried side chains, has hitherto been unfeasible in a reliable, automated manner, the MEP often displaying unphysical behavior, such as the crossing of bonds. Here, this problem is addressed by combining a counterintuitive procedure for generating an initial guess of the path, in which all side chains are shrunk, with the conjugate peak refinement (CPR) method. The effectiveness of the approach is tested on the conformational switch in Ras p21. This conformational transition involves some partial unfolding and re‐folding, a process for which a multitude of pathways are likely to exist and for which a single MEP does not provide a complete description. However, this transition requires some sterically demanding rearrangements, thus testing the ability of a method to find low‐energy pathways free of structurally unphysical events. This is achieved by the present approach, which finds a path whose rate‐limiting barrier is compatible with experiment. This demonstrates that the method can be used to compute plausible pathways for complex rearrangements in proteins in an automated manner that is unbiased by external driving constraints. Proteins 2005.