Frustration-guided motion planning reveals conformational transitions in proteins

Journal article


Publication Details

Author(s): Budday D, Fonseca R, Leyendecker S, van den Bedem H
Journal: Proteins-Structure Function and Bioinformatics
Publication year: 2017
Volume: 85
Journal issue: 10
Pages range: 1795-1807
ISSN: 0887-3585
Language: English


Abstract


sProteins exist as conformational ensembles, exchanging between substates to perform their func- tion. 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, we present a new, robotics-inspired motion planning procedure called dCC- RRT 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, 7.5 Å root mean square deviation (RMSD), our pathways reduced the Ca atom RMSD to the goal conformation by 78%, outperforming peer methods. 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 25 Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC- RRT can reveal detailed, all-atom molecular mechanisms for small and large amplitude motions. Source code and binaries are freely available at https://github.com/ExcitedStates/KGS/. gdfdfgdfProteins exist as conformational ensembles, exchanging between substates to perform their func-


tion. 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, we present a new, robotics-inspired motion planning procedure called dCC-


RRT 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, 7.5 Å root mean


square deviation (RMSD), our pathways reduced the Ca atom RMSD to the goal conformation by


78%, outperforming peer methods. 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 25 Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-


RRT can reveal detailed, all-atom molecular mechanisms for small and large amplitude motions.


Source code and binaries are freely available at https://github.com/ExcitedStates/KGS/.


FAU Authors / FAU Editors

Budday, Dominik
Chair of Applied Dynamics
Leyendecker, Sigrid Prof. Dr.-Ing.
Chair of Applied Dynamics


External institutions with authors

Stanford University


How to cite

APA:
Budday, D., Fonseca, R., Leyendecker, S., & van den Bedem, H. (2017). Frustration-guided motion planning reveals conformational transitions in proteins. Proteins-Structure Function and Bioinformatics, 85(10), 1795-1807. https://dx.doi.org/10.1002/prot.25333

MLA:
Budday, Dominik, et al. "Frustration-guided motion planning reveals conformational transitions in proteins." Proteins-Structure Function and Bioinformatics 85.10 (2017): 1795-1807.

BibTeX: 

Last updated on 2018-17-10 at 22:40