Protein Conformational Transitions from All-Atom Adaptively Biased Path Optimization

Journal of Chemical Theory and Computation
Heng Wu, Carol Beth Post

Abstract

Simulation methods are valuable for elucidating protein conformational transitions between functionally diverse states given that transition pathways are difficult to capture experimentally. Nonetheless, specific computational algorithms are required because of the high free energy barriers between these different protein conformational states. Adaptively biased path optimization (ABPO) is an unrestrained, transition-path optimization method that works in a reduced-variable space to construct an adaptive biasing potential to aid convergence. ABPO was previously applied using a coarse-grained Go̅-model to study conformational activation of Lyn, a Src family tyrosine kinase. How effectively ABPO can be applied at the higher resolution of an all-atom model to explore protein conformational transitions is not yet known. Here, we report the all-atom conformational transition paths of three protein systems constructed using the ABPO methodology. Two systems, triose phosphate isomerase and dihydrofolate reductase, undergo local flipping of a short loop that promotes ligand binding. The third system, estrogen receptor α ligand binding domain, has a helix that adopts different conformations when the protein is bound to an agonist or an ...Continue Reading

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Citations

Apr 24, 2020·Journal of Chemical Theory and Computation·Farzaneh JalalypourCanan Atilgan
Jun 20, 2020·Journal of Chemical Theory and Computation·Paul B OrndorffArjan van der Vaart

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