Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA 15213, USA.
J Gen Physiol. 2012 Jul;140(1):55-68. doi: 10.1085/jgp.201110766.
The interaction between membrane proteins and the surrounding membrane is becoming increasingly appreciated for its role in regulating protein function, protein localization, and membrane morphology. In particular, recent studies have suggested that membrane deformation is needed to stably accommodate proteins harboring charged amino acids in their transmembrane (TM) region, as it is energetically prohibitive to bury charge in the hydrophobic core of the bilayer. Unfortunately, current computational methods are poorly equipped for describing such deformations, as atomistic simulations are often too short to observe large-scale membrane reorganization and most continuum approaches assume a flat membrane. Previously, we developed a method that overcomes these shortcomings by using elasticity theory to characterize equilibrium membrane distortions in the presence of a TM protein, while using traditional continuum electrostatic and nonpolar energy models to determine the energy of the protein in the membrane. Here, we linked the elastostatics, electrostatics, and nonpolar numeric solvers to permit the calculation of energies for nontrivial membrane deformations. We then coupled this procedure to a robust search algorithm that identifies optimal membrane shapes for a TM protein of arbitrary chemical composition. This advance now permits us to explore a host of biological phenomena that were beyond the scope of our original method. We show that the energy required to embed charged residues in the membrane can be highly nonadditive, and our model provides a simple mechanical explanation for this nonadditivity. Our results also predict that isolated voltage sensor segments do not insert into rigid membranes, but membrane bending dramatically stabilizes these proteins in the bilayer despite their high charge content. Additionally, we use the model to explore hydrophobic mismatch with regard to nonpolar peptides and mechanosensitive channels. Our method is in quantitative agreement with molecular dynamics simulations at a tiny fraction of the computational cost.
膜蛋白与周围膜的相互作用在调节蛋白质功能、蛋白质定位和膜形态方面的作用正越来越受到重视。特别是，最近的研究表明，为了稳定容纳跨膜（TM）区域中带有带电氨基酸的蛋白质，需要膜变形，因为在双层膜的疏水区中埋藏电荷在能量上是不可行的。不幸的是，目前的计算方法在描述这种变形方面能力较差，因为原子模拟通常太短，无法观察到大尺度的膜重组，而大多数连续体方法则假设膜是平的。以前，我们开发了一种方法，通过使用弹性理论来描述 TM 蛋白存在时的平衡膜变形，同时使用传统的连续体静电和非极性能量模型来确定蛋白在膜中的能量，从而克服了这些缺点。在这里，我们将弹性静力学、静电学和非极性数值求解器链接起来，以允许计算非平凡膜变形的能量。然后，我们将此过程耦合到一个强大的搜索算法中，该算法可以为任意化学组成的 TM 蛋白识别最佳的膜形状。这一进展现在使我们能够探索许多超出我们原始方法范围的生物学现象。我们表明，将带电残基嵌入膜中所需的能量可能高度不可加，我们的模型为这种不可加性提供了一个简单的力学解释。我们的结果还预测，孤立的电压传感器段不会插入刚性膜中，但膜弯曲尽管其高电荷含量，却能极大地稳定这些蛋白质在双层膜中的位置。此外，我们还使用该模型研究了非极性肽和机械敏感通道的疏水性失配。我们的方法与分子动力学模拟在计算成本的一小部分上具有定量一致性。
