Conformational dynamics of a nicotinic receptor neurotransmitter binding site

Author:

Singh Mrityunjay1,Indurthi Dinesh C.2,Mittal Lovika1,Auerbach Anthony2,Asthana Shailendra1

Affiliation:

1. Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster

2. Department of Physiology and Biophysics, University at Buffalo, State University of New York

Abstract

Agonists activate receptors by interacting more strongly with active versus resting conformations of their target sites. For each ligand, the strong-weak binding free energy difference sets efficacy and the weak/strong ratio sets efficiency. We performed molecular dynamics simulations to explore the conformational dynamics of a nicotinic receptor neurotransmitter binding site in the weak→strong structural transition. The alternative conformations were identified by comparing calculated and experimental binding free energies for 4 agonists. In weak→strong, the agonist rotates about its cationic center (a ‘flip’), loop C moves in (a ‘flop’) to reposition αY190 to form a water-mediated cross-subunit hydrogen bond with the ligand. The flop restructures the aromatic core, and the flip increases van der Waals interactions to generate a more compact, hydrophobic and stable pocket. The simulations reveal a transient intermediate state as well as changes in a salt bridge that may distinguish agonists.

Publisher

eLife Sciences Publications, Ltd

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3