Folding- upon- binding pathways of an intrinsically disordered protein from a deep Markov state model

• 成果类型: Article
• 署名作者: Sisk, Thomas R.; Robustelli, Paul
• 署名单位: Dartmouth College
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13079
• DOI: 10.1073/pnas.2313360121
• 发表日期: 2024-02-06
• 关键词: c-terminal domain; measles-virus nucleoprotein; localize energetic frustration; molecular recognition features; fuzzy complexes; nonnative interactions; variational approach; functional dynamics; upon-binding; TRANSITION

摘要

A central challenge in the study of intrinsically disordered proteins is the characterization of the mechanisms by which they bind their physiological interaction partners. Here, we utilize a deep learning-based Markov state modeling approach to characterize the folding- upon- binding pathways observed in a long timescale molecular dynamics simulation of a disordered region of the measles virus nucleoprotein NTAIL reversibly binding the X domain of the measles virus phosphoprotein complex. We find that folding- upon- binding predominantly occurs via two distinct encounter complexes that are differentiated by the binding orientation, helical content, and conformational heterogeneity of NTAIL. We observe that folding- upon- binding predominantly proceeds through a multi-step induced fit mechanism with several intermediates and do not find evidence for the existence of canonical conformational selection pathways. We observe four kinetically separated native-like bound states that interconvert on timescales of eighty to five hundred nanoseconds. These bound states share a core set of native intermolecular contacts and stable NTAIL helices and are differentiated by a sequential formation of native and non- native contacts and additional helical turns. Our analyses provide an atomic resolution structural description of intermediate states in a folding- upon- binding pathway and elucidate the nature of the kinetic barriers between metastable states in a dynamic and heterogenous, or fuzzy, protein complex.