Im Wonpil, Brooks Charles L
Department of Molecular Biology (TPC6) and Center for Theoretical Biological Physics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6771-6. doi: 10.1073/pnas.0408135102. Epub 2005 Apr 28.
The mechanism of interfacial folding and membrane insertion of designed peptides is explored by using an implicit membrane generalized Born model and replica-exchange molecular dynamics. Folding/insertion simulations initiated from fully extended peptide conformations in the aqueous phase, at least 28 A away from the membrane interface, demonstrate a general mechanism for structure formation and insertion (when it occurs). The predominately hydrophobic peptides from the synthetic WALP and TMX series first become localized at the membrane-solvent interface where they form significant helical secondary structure via a helix-turn-helix motif that inserts the central hydrophobic residues into the membrane interior, and then fluctuations occur that provide a persistent helical structure throughout the peptide and it inserts with its N-terminal end moving across the membrane. More specifically, we observed that: (i) the WALP peptides (WALP16, WALP19, and WALP23) spontaneously insert in the membrane as just noted; (ii) TMX-1 also inserts spontaneously after a similar mechanism and forms a transmembrane helix with a population of approximately 50% at 300 K; and (iii) TMX-3 does not insert, but exists in a fluctuating membrane interface-bound form. These findings are in excellent agreement with available experimental data and demonstrate the potential for new implicit solvent/membrane models together with advanced simulation protocols to guide experimental programs in exploring the nature and mechanism of membrane-associated folding and insertion of biologically important peptides.
通过使用隐式膜广义玻恩模型和副本交换分子动力学，探索了设计肽的界面折叠和膜插入机制。从水相中至少距膜界面28埃的完全伸展肽构象开始的折叠/插入模拟，展示了结构形成和插入（当发生时）的一般机制。来自合成的WALP和TMX系列的主要疏水肽首先定位于膜-溶剂界面，在那里它们通过螺旋-转角-螺旋基序形成显著的螺旋二级结构，将中央疏水残基插入膜内部，然后发生波动，在整个肽中提供持久的螺旋结构，并且其N末端穿过膜插入。更具体地说，我们观察到：（i）如前所述，WALP肽（WALP16、WALP19和WALP23）自发插入膜中；（ii）TMX-1在类似机制后也自发插入，并在300K时形成约50%群体的跨膜螺旋；（iii）TMX-3不插入，而是以波动的膜界面结合形式存在。这些发现与现有实验数据非常吻合，并证明了新的隐式溶剂/膜模型以及先进的模拟协议在指导实验程序探索生物学上重要肽的膜相关折叠和插入的性质和机制方面的潜力。
