Molecular Modeling of Biological Nanopores

匹兹堡大学的Rob Coalson得到了化学部化学理论、模型和计算方法计划的支持，该计划旨在对生物离子通道和纳米孔进行计算和理论研究。分子和细胞生物科学部的细胞动力学和功能计划为该奖项做出了贡献。该细胞使用由脂质双层组成的膜来分隔其内容物。特殊的蛋白质插入细胞膜，并允许生理功能所需的物质通过细胞膜运输。对于细胞膜，相关的膜结合蛋白称为离子通道。它们选择性地通过细胞膜传递离子，对于神经信号传播、肌肉收缩、细胞体积的自动调节和胰岛素等生物化学物质的产生是必不可少的。大核孔复合体(NPC)在调节分子物质流入和流出真核细胞的过程中起着类似的作用。核祖细胞位于核膜上，控制着包括蛋白质和RNA在内的大分子生物分子在细胞核和细胞质之间的流动。在这里开展的工作需要使用适当水平的原子分辨率，对通过这些生物纳米孔的材料流动进行大规模计算机模拟，重点放在控制这些运输现象的分子机制上。它对基础分子生物学具有重要意义，最终可能与医学相关，因为严重的疾病与离子通道和鼻咽癌细胞的不正常功能有关。当跨越双层膜的蛋白质通道处于开放状态(即，以适当的水孔为特征)时，离子被由跨膜的浓度或电势差产生的电化学梯度驱动通过。通道选通是一个更复杂的过程。大多数门在毫秒到几秒的时间尺度上运行，太长了，无法通过蛮力全原子分子动力学模拟来模拟。理解这些过程需要开发新的跨尺度计算技术。另一类耐人寻味的生物纳米孔是由跨越真核细胞核膜的大型蛋白质复合体组成。这些核孔复合体(NPC)的大小和复杂性给分子模拟分析带来了重大挑战。离子通道建模工作将采用一种新的分而治之的多尺度建模方法。从相对较短的全原子分子动力学模拟中提取的分子水平细节将被提供给粗粒度的动力学模型。除了通过真实的通道蛋白质三维模型计算离子渗透外，还将解决离子通道门控机制以及渗透和门控之间的耦合等问题。核电厂的工作需要开发以物理化学为基础的粗粒度模拟模型，并结合统计力学分析。这些工具将使研究比原子分子动力学模拟所能获得的更大的系统和更长的时间尺度成为可能，即介观尺度，其中许多大分子的集体行为影响孔选择分子货物通过它的能力。

Rob Coalson of the University of Pittsburgh is supported by the Chemical Theory, Models and Computational Methods program in the Chemistry Division for computational and theoretical studies of biological ion channels and nanopores. The Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences contributes to the award. The cell uses membranes composed of lipid bilayers to compartmentalize its contents. Specialized proteins insert into the membrane and allow transport through it as required for physiological function. For the cell membrane, the relevant membrane- bound proteins are called ion channels. They selectively pass ions through the membrane and are essential for nerve signal propagation, muscle contraction, auto-regulation of cell volume and production of biochemicals like insulin. The large Nuclear Pore Complex (NPC) plays a similar role in regulating the flow of molecular material into and out of the nucleus of eukaryotic cells. Residing in the nuclear membrane, NPCs controlthe flow of large biomolecules including proteins and RNAs between the cell nucleus and its cytoplasm. The work to be undertaken here entails large-scale computer simulations of the flow of material through these biological nanopores, using an appropriate level of atomic resolution, focusing on the molecular mechanisms that control these transport phenomena. It has importance for fundamental molecular biology, and ultimately may have relevance to medicine, as serious diseases are associated with improper function of ion channels and NPCs. When a protein channel spanning a bilayer membrane is in its open state (i.e., is characterized by an appropriate aqueous pore), ions are driven through itby an electrochemical gradient which arises either from a concentration or an electrical potential difference across the membrane. Channel gating is a more complex process. Most gates operate on a time scale of milliseconds to seconds, too long to be simulated via brute force all atom Molecular Dynamics simulation. Understanding these processes requires the development of novel scale-spanning computational techniques. Another intriguing class of biological nanopores is comprised of large protein complexes which span the nuclear envelope in eukaryotic cells. The size and complexity of these Nuclear Pore Complexes (NPCs) present major challenges to molecular modeling analysis. The work to be performed on ion channel modeling will employ a novel divide and conquer multi-scale modeling approach. Molecular level detail extracted from relatively short all-atom Molecular Dynamics simulations will be fed into coarse-grained kinetic models. In addition to calculating ion permeation through realistic 3D models of channel proteins, problems involving mechanisms of ion channel gating and the coupling between permeation and gating will be tackled. The work on NPCs entails development of physico-chemically grounded coarse-grained simulation models combined with statistical mechanical analysis. These tools will enable study of larger systems and longer time scales than can be accessed by atomistic Molecular Dynamics simulations, namely, mesoscopic scales where collective behavior of many large molecules impacts the pore's ability to select molecular cargos to pass through it.