Insights into the recognition and association of transmembrane α-helices.: The free energy of α-helix dimerization in glycophorin A
Insights into the recognition and association of transmembrane α-helices.: The free energy of α-helix dimerization in glycophorin A
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DOI：
10.1021/ja050581y
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发表时间：
2005-06-15
影响因子：
15
通讯作者：
Chipot, C
中科院分区：
文献类型：
--
作者：
Hénin, J;Pohorille, A;Chipot, C
在膜模拟物中，从125 ns的分子动力学（MID）模拟中估计血型糖蛋白A的跨膜（TM）区域的α-螺旋二聚化的自由能。自由能分布是通过允许TM螺旋段沿反应途径可逆地沿着扩散而获得的。将平均力的势分解为自由能分量，阐明了α-螺旋识别和结合的关键步骤。在大分离时，TM片段被溶剂推到一起，允许发生初始但不一定是天然的螺旋间相互作用。这个早期识别阶段先于天然接触的形成，天然接触伴随着螺旋的倾斜，这是二聚体结构的特征。该步骤主要由货车范德华螺旋-螺旋相互作用驱动。自由能微扰计算的L75 A和I76 A点突变揭示了破坏螺旋-螺旋协会由于有利的分散相互作用的损失。额外的MID模拟的天然TM二聚体和一个单一的α-螺旋证实，在协会之前，个别α-螺旋是独立稳定的，在协议的“两阶段”模型的完整膜蛋白折叠。
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.