Ramakrishnan N, Sunil Kumar P B, Radhakrishnan Ravi
Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA-19104.
Department of Physics, Indian Institute of Technology Madras, Chennai, India - 600036.
Phys Rep. 2014 Oct 1;543(1):1-60. doi: 10.1016/j.physrep.2014.05.001.
Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across the various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham - Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this description, the protein is expressed in the form of a spontaneous curvature field. The approaches include field theoretical methods limited to the small deformation regime, triangulated surfaces and particle-based computational models to investigate the large-deformation regimes observed in the natural state of many biological membranes. Applications of these methods to understand the properties of biological membranes in homogeneous and inhomogeneous environments of proteins, whose underlying curvature fields are either isotropic or anisotropic, are discussed. The diversity in the curvature fields elicits a rich variety of morphological states, including tubes, discs, branched tubes, and caveola. Mapping the thermodynamic stability of these states as a function of tuning parameters such as concentration and strength of curvature induction of the proteins is discussed. The relative stabilities of these self-organized shapes are examined through free-energy calculations. The suite of methods discussed here can be tailored to applications in specific cellular settings such as endocytosis during cargo trafficking and tubulation of filopodial structures in migrating cells, which makes these methods a powerful complement to experimental studies.
生物膜构成了细胞和细胞器的边界。这些膜是柔软的流体界面,其热力学状态由弯曲模量、诱导曲率场和热涨落决定。最近,大量实验证据表明这些结构在许多细胞过程中发挥着积极作用,从货物运输到细胞运动。据信,局部膜曲率由于其与附着在其表面的无数蛋白质和其他大分子的相互作用而不断改变,是这些细胞过程中出现功能的关键。原子尺度的机制由蛋白质 - 脂质相互作用强度、脂质组成、蛋白质附近的脂质分布、蛋白质的形状和氨基酸组成以及其氨基酸含量决定。分子相互作用的特异性以及多种蛋白质的协同作用在中尺度上诱导并稳定复杂的膜形状。这些形状范围广泛,从球形质膜到高尔基体的复杂囊泡。绘制分子尺度上蛋白质诱导的变形与由此产生的中尺度形态之间的关系,是跨越不同长度尺度连接细胞实验的关键。在这篇综述中,我们专注于用于理解蛋白质驱动的膜重塑背后现象学的理论和计算方法。分子尺度上的相互作用可以通过全原子和粗粒化分子动力学(MD,CGMD)以及耗散粒子动力学(DPD)模拟进行计算探测,我们仅简要描述。我们选择专注于几种连续介质方法,这些方法扩展了用于膜的Canham - Helfrich弹性能量模型,以包括曲率诱导蛋白的影响,并探索此类系统的构象相空间。在这种描述中,蛋白质以自发曲率场的形式表示。这些方法包括限于小变形 regime 的场论方法、三角化表面和基于粒子的计算模型,以研究在许多生物膜自然状态下观察到的大变形 regime。讨论了这些方法在理解蛋白质均匀和非均匀环境中生物膜性质方面的应用,其潜在的曲率场要么是各向同性的要么是各向异性的。曲率场的多样性引发了丰富多样的形态状态,包括管子、圆盘、分支管子和小窝。讨论了将这些状态的热力学稳定性映射为诸如蛋白质浓度和曲率诱导强度等调节参数的函数。通过自由能计算检查这些自组织形状的相对稳定性。这里讨论的这套方法可以针对特定细胞环境中的应用进行定制,例如货物运输过程中的内吞作用和迁移细胞中丝状伪足结构的管状化,这使得这些方法成为实验研究的有力补充。