Mechanism of phosphate release from actin filaments

• 成果类型: Article
• 署名作者: Wang, Yihang; Wu, Jiangbo; Zsolnay, Vilmos; Pollard, Thomas D.; Voth, Gregory A.
• 署名单位: University of Chicago; University of Chicago; Yale University; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13456
• DOI: 10.1073/pnas.2408156121
• 发表日期: 2024-07-16
• 关键词: molecular-dynamics; atp hydrolysis; software news; polymerization; nucleotide; adp; metadynamics; fluctuations; flexibility; kinetics

摘要

After ATP- actin monomers assemble filaments, the ATP's y- phosphate is hydrolyzedwithin seconds and dissociates over minutes. We used all- atom molecular dynamics simulations to sample the release of phosphate from filaments and study residues that gate release. Dissociation of phosphate from Mg2+is 2+ is rate limiting and associated with an energy barrier of 20 kcal/mol, consistent with experimental rates of phosphate release. Phosphate then diffuses within an internal cavity toward a gate formed by R177, as suggested in prior computational studies and cryo- EM- EM structures. The gate is closed when R177 hydrogen bonds with N111 and is open when R177 forms a salt bridge with D179. Most of the time, interactions of R177 with other residues occlude the phosphate release pathway. Machine learning analysis reveals that the occluding interactions fluctuate rapidly, underscoring the secondary role of backdoor gate opening in Pi i release, in contrast with the previous hypothesis that gate opening is the primary event.