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Title: Frustration-guided motion planning reveals conformational transitions in proteins

Proteins exist as conformational ensembles, exchanging between substates to perform their function. Advances in experimental techniques yield unprecedented access to structural snapshots of their conformational landscape. However, computationally modeling how proteins use collective motions to transition between substates is challenging owing to a rugged landscape and large energy barriers. Here in this paper, we present a new, robotics-inspired motion planning procedure called dCCRRT that navigates the rugged landscape between substates by introducing dynamic, interatomic constraints to modulate frustration. The constraints balance non-native contacts and flexibility, and instantaneously redirect the motion towards sterically favorable conformations. On a test set of eight proteins determined in two conformations separated by, on average, 7.5Å root mean square deviation (RMSD), our pathways reduced the Cα atom RMSD to the goal conformation by 78%, outperforming peer methods. Additionally, we then applied dCC-RRT to examine how collective, small-scale motions of four side-chains in the active site of cyclophilin A propagate through the protein. dCC-RRT uncovered a spatially contiguous network of residues linked by steric interactions and collective motion connecting the active site to a recently proposed, non-canonical capsid binding site 25Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-RRT can reveal detailed, all-atom molecular mechanismsmore » for small and large amplitude motions.Source code and binaries are freely available at« less
 [1] ;  [2] ;  [1] ; ORCiD logo [3]
  1. University of Erlangen-Nuremberg, Erlangen (Germany). Chair of Applied Dynamics
  2. Stanford Univ., CA (United States). Department of Molecular and Cellular Physiology; SLAC National Accelerator Lab., Menlo Park, CA (United States). Biosciences Division
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States). Biosciences Division
Publication Date:
Grant/Contract Number:
AC02-76SF00515; 7, 2014-1; NNF15OC0015268
Accepted Manuscript
Journal Name:
Additional Journal Information:
Journal Volume: 85; Journal Issue: 10; Journal ID: ISSN 0887-3585
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; cyclophilin A; dynamic clash constraints (dCC); Gas; Kino-Geometric sampling (KGS); protein conformational transitions; RRT motion planning
OSTI Identifier: