Argudo David, Bethel Neville P, Marcoline Frank V, Wolgemuth Charles W, Grabe Michael
Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California.
Departments of Molecular and Cellular Biology and Physics, University of Arizona, Tucson, Arizona.
Biophys J. 2017 May 23;112(10):2159-2172. doi: 10.1016/j.bpj.2017.03.040.
The influence of the membrane on transmembrane proteins is central to a number of biological phenomena, notably the gating of stretch activated ion channels. Conversely, membrane proteins can influence the bilayer, leading to the stabilization of particular membrane shapes, topological changes that occur during vesicle fission and fusion, and shape-dependent protein aggregation. Continuum elastic models of the membrane have been widely used to study protein-membrane interactions. These mathematical approaches produce physically interpretable membrane shapes, energy estimates for the cost of deformation, and a snapshot of the equilibrium configuration. Moreover, elastic models are much less computationally demanding than fully atomistic and coarse-grained simulation methodologies; however, it has been argued that continuum models cannot reproduce the distortions observed in fully atomistic molecular dynamics simulations. We suggest that this failure can be overcome by using chemically and geometrically accurate representations of the protein. Here, we present a fast and reliable hybrid continuum-atomistic model that couples the protein to the membrane. We show that the model is in excellent agreement with fully atomistic simulations of the ion channel gramicidin embedded in a POPC membrane. Our continuum calculations not only reproduce the membrane distortions produced by the channel but also accurately determine the channel's orientation. Finally, we use our method to investigate the role of membrane bending around the charged voltage sensors of the transient receptor potential cation channel TRPV1. We find that membrane deformation significantly stabilizes the energy of insertion of TRPV1 by exposing charged residues on the S4 segment to solution.
膜对跨膜蛋白的影响是许多生物学现象的核心，尤其是拉伸激活离子通道的门控。相反，膜蛋白可以影响双层膜，导致特定膜形状的稳定、囊泡裂变和融合过程中发生的拓扑变化以及形状依赖性蛋白聚集。膜的连续弹性模型已被广泛用于研究蛋白 - 膜相互作用。这些数学方法产生了具有物理可解释性的膜形状、变形成本的能量估计以及平衡构型的快照。此外，弹性模型在计算上比完全原子和粗粒度模拟方法要求低得多；然而，有人认为连续模型无法重现完全原子分子动力学模拟中观察到的扭曲。我们认为，通过使用化学和几何上准确的蛋白表示可以克服这种不足。在这里，我们提出了一种快速且可靠的混合连续 - 原子模型，该模型将蛋白与膜耦合。我们表明，该模型与嵌入在POPC膜中的离子通道短杆菌肽的完全原子模拟结果非常吻合。我们的连续计算不仅重现了通道产生的膜扭曲，还准确地确定了通道的方向。最后，我们使用我们的方法研究膜围绕瞬时受体电位阳离子通道TRPV1的带电电压传感器弯曲的作用。我们发现，膜变形通过将S4段上的带电残基暴露于溶液中，显著稳定了TRPV1插入的能量。
