Department of Biochemistry, University of Oxford, United Kingdom.
Biophys J. 2011 Jan 19;100(2):410-9. doi: 10.1016/j.bpj.2010.12.3682.
Most membrane proteins contain a transmembrane (TM) domain made up of a bundle of lipid-bilayer-spanning α-helices. TM α-helices are generally composed of a core of largely hydrophobic amino acids, with basic and aromatic amino acids at each end of the helix forming interactions with the lipid headgroups and water. In contrast, the S4 helix of ion channel voltage sensor (VS) domains contains four or five basic (largely arginine) side chains along its length and yet adopts a TM orientation as part of an independently stable VS domain. Multiscale molecular dynamics simulations are used to explore how a charged TM S4 α-helix may be stabilized in a lipid bilayer, which is of relevance in the context of mechanisms of translocon-mediated insertion of S4. Free-energy profiles for insertion of the S4 helix into a phospholipid bilayer suggest that it is thermodynamically favorable for S4 to insert from water to the center of the membrane, where the helix adopts a TM orientation. This is consistent with crystal structures of Kv channels, biophysical studies of isolated VS domains in lipid bilayers, and studies of translocon-mediated S4 helix insertion. Decomposition of the free-energy profiles reveals the underlying physical basis for TM stability, whereby the preference of the hydrophobic residues of S4 to enter the bilayer dominates over the free-energy penalty for inserting charged residues, accompanied by local distortion of the bilayer and penetration of waters. We show that the unique combination of charged and hydrophobic residues in S4 allows it to insert stably into the membrane.
大多数膜蛋白都包含一个由脂质双层跨膜（TM）α-螺旋组成的跨膜（TM）结构域。TM α-螺旋通常由核心区域的大量疏水性氨基酸组成，螺旋两端的碱性和芳香族氨基酸与脂质头部基团和水分子形成相互作用。相比之下，离子通道电压传感器（VS）结构域的 S4 螺旋在其长度上包含四个或五个碱性（主要是精氨酸）侧链，但作为独立稳定的 VS 结构域的一部分，它采用 TM 取向。多尺度分子动力学模拟用于研究带电荷的 TM S4 α-螺旋如何在脂质双层中稳定，这与易位子介导的 S4 插入机制有关。S4 螺旋插入磷脂双层的自由能曲线表明，S4 从水中插入到膜的中心是热力学有利的，在那里螺旋采用 TM 取向。这与 Kv 通道的晶体结构、脂质双层中分离的 VS 结构域的生物物理研究以及易位子介导的 S4 螺旋插入研究一致。自由能曲线的分解揭示了 TM 稳定性的潜在物理基础，即 S4 疏水性残基进入双层的偏好超过插入带电荷残基的自由能罚分，同时伴有双层的局部变形和水分子的穿透。我们表明，S4 中带电荷和疏水性残基的独特组合允许其稳定插入膜中。
