A direct computational assessment of vinculin-actin unbinding kinetics reveals catch-bonding behavior

• 成果类型: Article
• 署名作者: Ccoa, Willmor J. Pena; Mukadum, Fatemah; Ramon, Aubin; Stirnemann, Guillaume; Hocky, Glen M.
• 署名单位: New York University; University of Cambridge; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite PSL; Ecole Normale Superieure (ENS); New York University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12692
• DOI: 10.1073/pnas.2425982122
• 发表日期: 2025-05-27
• 关键词: molecular-dynamics; FORCE; adhesion; cell; simulations; TRANSITION; plasticity; mechanics; filaments; pathways

摘要

Vinculin forms a catch bond with the cytoskeletal polymer actin, displaying an increased bond lifetime upon force application. Notably, this behavior depends on the direction of the applied force, which has significant implications for cellular mechanotransduction. In this work, we present a comprehensive molecular dynamics simulation study, employing enhanced sampling techniques to investigate the thermodynamic, kinetic, and mechanistic aspects of this phenomenon at physiologically relevant forces. We dissect a catch bond mechanism in which force shifts vinculin between either a weakly or strongly bound state. Our results demonstrate that models for these states have unbinding times consistent with those from single-molecule studies, and suggest that both have some intrinsic catch-bonding behavior. We provide atomistic insight into this behavior, and show how a directional pulling force can promote the strong or weak state. Crucially, our strategy can be extended to measure the difficult-to-capture effects of small mechanical forces on biomolecular systems in general, and those involved in mechanotransduction more specifically.