期刊
PLOS COMPUTATIONAL BIOLOGY
卷 15, 期 1, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1006689
关键词
-
资金
- National Institutes of Health [DA026434, DA045473, DA034049, DA07242, DA06241, CA08748]
- Peter F. McManus Charitable Trust
- Mayday Fund
- National Science Foundation [ACI-1548562, MCB080077]
- NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [K02DA026434, R01DA007242, R01DA034049, R01DA006241] Funding Source: NIH RePORTER
The differential modulation of agonist and antagonist binding to opioid receptors (ORs) by sodium (Na+) has been known for decades. To shed light on the molecular determinants, thermodynamics, and kinetics of Na+ translocation through the mu-OR (MOR), we used a multi-ensemble Markov model framework combining equilibrium and non-equilibrium atomistic molecular dynamics simulations of Na+ binding to MOR active or inactive crystal structures embedded in an explicit lipid bilayer. We identify an energetically favorable, continuous ion pathway through the MOR active conformation only, and provide, for the first time: i) estimates of the energy differences and required timescales of Na+ translocation in inactive and active MORs, ii) estimates of Na+-induced changes to agonist binding validated by radioligand measurements, and iii) testable hypotheses of molecular determinants and correlated motions involved in this translocation, which are likely to play a key role in MOR signaling.
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