Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 141, Issue 37, Pages 14752-14763Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b06776
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Funding
- EU [NMP4-SL-2013-604530]
- Nanosystems Initiative Munich
- ERC
- ERC Starting Grant [715207]
- National Institutes of Health (NIH) [P41-GM104601]
- National Science Foundation (NSF) [MCB-1616590]
- Energy Biosciences Institute
- NERSC/Edison supercomputers as part of the DoE ALCC program
- DOE Office of Science User Facility [DE-ACO2-06CH11357]
- Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]
- Petascale Computational Resource (PRAC)
- National Science Foundation [OCI-0725070, ACI-1238993, ACT-1713784]
- state of Illinois
- Center for Macro molecular Modeling and Bioinformatics
- Molecular Modeling of Bioenergetic Systems
- European Research Council (ERC) [715207] Funding Source: European Research Council (ERC)
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Can molecular dynamics simulations predict the mechanical behavior of protein complexes? Can simulations decipher the role of protein domains of unknown function in large macromolecular complexes? Here, we employ a wide-sampling computational approach to demonstrate that molecular dynamics simulations, when carefully performed and combined with single-molecule atomic force spectroscopy experiments, can predict and explain the behavior of highly mechanostable protein complexes. As a test case, we studied a previously unreported homologue from Ruminococcus flavefaciens called X-module-Dockerin (XDoc) bound to its partner Cohesin (Coh). By performing dozens of short simulation replicas near the rupture event, and analyzing dynamic network fluctuations, we were able to generate large simulation statistics and directly compare them with experiments to uncover the mechanisms involved in mechanical stabilization. Our single-molecule force spectroscopy experiments show that the XDoc-Coh homologue complex withstands forces up to 1 nN at loading rates of 10(5) pN/s. Our simulation results reveal that this remarkable mechanical stability is achieved by a protein architecture that directs molecular deformation along paths that run perpendicular to the pulling axis. The X-module was found to play a crucial role in shielding the adjacent protein complex from mechanical rupture. These mechanisms of protein mechanical stabilization have potential applications in biotechnology for the development of systems exhibiting shear enhanced adhesion or tunable mechanics.
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