期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 37, 页码 18404-18409出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904707116
关键词
protein-ligand interaction; protein kinase; free-energy landscape; molecular dynamics simulation; replica-exchange molecular dynamics
资金
- High Performance Computing Infrastructure system [hp150270, hp160207, hp170115, hp170254, hp180201, hp180274, hp190181]
- MEXT
- MEXT [26119006]
- MEXT/JSPS KAKENHI [26220807, 19H05645, 19K12229]
- RIKEN pioneering project Dynamic Structural Biology
- Center of Innovation Program from Japan Science and Technology Agency
- Grants-in-Aid for Scientific Research [19H05645, 26220807, 19K12229] Funding Source: KAKEN
Modern drug discovery increasingly focuses on the drug-target binding kinetics which depend on drug (un) binding pathways. The conventional molecular dynamics simulation can observe only a few binding events even using the fastest supercomputer. Here, we develop 2D gREST/REUS simulation with enhanced flexibility of the ligand and the protein binding site. Simulation (43 mu s in total) applied to an inhibitor binding to c-Src kinase covers 100 binding and unbinding events. On the statistically converged free-energy landscapes, we succeed in predicting the X-ray binding structure, including water positions. Furthermore, we characterize hidden semibound poses and transient encounter complexes on the free-energy landscapes. Regulatory residues distant from the catalytic core are responsible for the initial inhibitor uptake and regulation of subsequent bindings, which was unresolved by experiments. Stabilizing/blocking of either the semibound poses or the encounter complexes can be an effective strategy to optimize drug-target residence time.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据