Insights into the recognition and association of transmembrane α-helices.: The free energy of α-helix dimerization in glycophorin A

被引:130
作者
Hénin, J
Pohorille, A
Chipot, C
机构
[1] Univ Henri Poincare, Inst Nanceien Chim Mol, CNRS, UMR 7565,Equipe Dynam Assemblages Membranaires, F-54506 Vandoeuvre Les Nancy, France
[2] NASA, Ames Res Ctr, Exobiol Branch, Moffett Field, CA 94035 USA
关键词
D O I
10.1021/ja050581y
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The free energy of alpha-helix dimerization of the transmembrane (TM) region of glycophorin A was estimated from a 125-ns molecular dynamics (MID) simulation in a membrane mimetic. The free energy profile was obtained by allowing the TM helical segments to diffuse reversibly along the reaction pathway. Partition of the potential of mean force into free energy components illuminates the critical steps of alpha-helix recognition and association. At large separations, the TM segments are pushed together by the solvent, allowing initial, but not necessarily native, interhelical interactions to occur. This early recognition stage precedes the formation of native contacts, which is accompanied by a tilt of the helices, characteristic of the dimeric structure. This step is primarily driven by the van der Waals helix-helix interactions. Free energy perturbation calculations of the L75A and I76A point mutations reveal a disruption in helix-helix association due to a loss of favorable dispersion interactions. Additional MID simulations of the native TM dimer and of a single alpha-helix confirm that, prior to association, individual alpha-helices are independently stable, in agreement with the "two-stage" model of integral membrane protein folding.
引用
收藏
页码:8478 / 8484
页数:7
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