Coarse-Grained Free-Energy Simulations of Conformational State Transitions in an Adenosine 5′-Triphosphate-binding Cassette Exporter  

粗粒化自由能模拟研究ABC输出蛋白质构象态转变

作　　者：Yun Huang Hao-chen Xu Jie-lou Liao 黄云;徐浩琛;廖结楼(中国科学技术大学化学物理系,合肥230026)

机构地区：[1]Department of Chemical Physics,University of Science and Technology of China,Hefei 230026,China

出　　处：《Chinese Journal of Chemical Physics》2020年第6期712-716,I0002,共6页化学物理学报（英文）

基　　金：supported by the National Natu-ral Science Foundation of China(No.21073170 and No.21273209).

摘　　要：ATP-binding cassette exporters transport many substrates out of cellular membranes via alternating between inward-facing and outward-facing conformations. Despite extensive research efforts over the past decades, understanding of the molecular mechanism remains elusive. As these large-scale conformational movements are global and collective, we have previously performed extensive coarse-grained molecular dynamics simulations of the potential of mean force along the conformational transition pathway [J. Phys. Chem. B 119, 1295(2015)]. However, the occluded conformational state, in which both the internal and external gate are closed, was not determined in the calculated free energy profile. In this work, we extend the above methods to the calculation of the free energy profile along the reaction coordinate, d1-d2, which are the COM distances between the two sides of the internal(d1)and the external gate(d2). The potential of mean force is thus obtained to identify the transition pathway, along which several outward-facing, inward-facing, and occluded state structures are predicted in good agreement with structural experiments. Our coarse-grained molecular dynamics free-energy simulations demonstrate that the internal gate is closed before the external gate is open during the inward-facing to outward-facing transition and vice versa during the inward-facing to outward-facing transition. Our results capture the unidirectional feature of substrate translocation via the exporter, which is functionally important in biology. This finding is different from the previous result, in which both the internal and external gates are open reported in an X-ray experiment [Proc. Natl. Acad. Sci. USA 104,19005(2007)]. Our study sheds light on the molecular mechanism of the state transitions in an ATP-binding cassette exporter.

关 键 词：ATP-binding cassette exporter Conformational state transition Coarse-grained molecular dynamics Potential of mean force 

分 类 号：O643.1[理学—物理化学]