文献类型：期刊文献

英文题名：Exploring coumarin egress channels in human cytochrome P450 2A6 by random acceleration and steered molecular dynamics simulations

作者：Li, Weihua[1];Shen, Jie[1];Liu, Guixia[1];Tang, Yun[1];Hoshino, Tyuji[2]

机构：[1]E China Univ Sci & Technol, Dept Pharmaceut Sci, Sch Pharm, Shanghai 200237, Peoples R China;[2]Chiba Univ, Grad Sch Pharmaceut Sci, Chiba 2638522, Japan

年份：2011

卷号：79

期号：1

起止页码：271

外文期刊名：PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000285884100021)】；

基金：Grant sponsor: Shanghai Natural Science Foundation; Grant number: 10ZR1407000; Grant sponsor: Science Foundation for the Excellent Youth Scholars of East China University of Science and Technology; Grant number: YC0157115); Grant sponsor: Program for New Century Excellent Talents in University; Grant number: NCET-08-0774; Grant sponsor: National S&T Major Project of China; Grant number: 2009ZX09501-001.

语种：英文

外文关键词：P450 2A6; coumarin; egress channel; molecular dynamics; channel selectivity

摘要：The kinetic analysis of coumarin oxidation by CYP2A6 suggested that substrate binding and release occurred in the multiple steps and such events proceeded rapidly. However, the crystal structure of the CYP2A6-coumarin complex reveals that no obvious channel is open enough to allow coumarin to pass through. Thus, an intriguing and important question arises: how coumarin enters and exits the active site, which is deeply buried at the center of CYP2A6 fold. In this study, geometric analysis of the potential openings was first performed on all the available crystal structures of CYP2A6. And then, random acceleration molecular dynamics simulations were used to explore the possible substrate egress channels in CYP2A6. Two channels were most frequently observed. Afterwards, steered molecular dynamics simulations were performed and potentials of mean force were constructed to compare the preference of the two channels serving as the substrate egress channel. The results showed that channel 2c, which is located between helices I and G and the helix B'-C region, was the most likely channel for coumarin egress. The opening of channel 2c was characterized by a rotation of Phe111 together with a bending of helix B'. Our findings will not only be helpful for understanding the unbinding mechanism of coumarin and for identifying structural determinants related to the biological function of CYP2A6, but also provide further insight into the channel selectivity of P450s. Proteins 2011; 79: 271-281. (C) 2010 Wiley-Liss, Inc.