Computing Reaction Pathways of Rare Biomolecular Transitions using Atomistic Force-Fields

•Numerical simulations of protein folding are extremely difficult by plain MD and, to date, only limited to relatively small chains, performed on a special-purpose computer (ANTON)•The dominant reaction pathways is a path integral based approximate variational approach which focuses on the reactive part of the dynamics. In this method, folding trajectories for arbitrary proteins can be obtained using state-of-theart all-atom force fields•The approach was validated against plain MD results performed on ANTON and then applied to larger systems, which cannot be investigated using MD, even on ANTON.

The Dominant Reaction Pathway (DRP) method is an approximate variational scheme which can be used to compute reaction pathways in conformational transitions undergone by large biomolecules (up to ~ 103 amino-acids) using realistic all-atom force fields. We first review the status of development of this method. Next, we discuss its validation against the results of plain MD protein folding simulations performed by the DE-Shaw group using the Anton supercomputer. Finally, we review a few representative applications of the DRP approach to study reactions which are far too complex and rare to be investigated by plain MD, even on the Anton machine.

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