Multi-scale models of solute and ion transport in membrane proteins and artificial nanopores

拟议的研究计划的主题是现代建模方法的开发和应用，以了解膜蛋白和纳米孔中的溶质转运。有许多复杂的实验方法来测量分子与纳米孔和膜蛋白的行为、形状和相互作用的各个方面。控制特定离子和溶质运输的分子机制是细胞调节系统的主要组成部分，其定义了营养物质和渗透剂、细胞信号传导和生物电产生的递送途径。跨膜蛋白定义了生物膜的显著机械和电学性质，在扩散极限或接近扩散极限时显示出令人惊讶的复杂物理行为和选择性（分选溶质的能力）。转运蛋白的动力学通过未知的机制与它们穿过细胞膜的特定货物密切相关。过去，各种膜蛋白被用于直接生物技术应用，并作为生物启发材料（例如质子纳米线）的模板。系统的大小和复杂细胞环境的多个混杂因素代表了仅从实验观察解释溶质转运的分子机制的重大挑战。使用强大的计算机和原子如何相互作用的描述，可以计算生物分子在时间上如何移动和相互作用的原子细节。该研究项目旨在开发和应用分子的计算模型，以更好地了解窄和宽生物孔中溶质传输的热力学和动力学。我们在开发自由能表面有效采样的理论和方法以及开发直接建模和解释纳米孔实验数据的方法方面取得了重大进展。我们处于一个独特的位置，研究运输过程中的各种水平的分辨率从电子自由度相关的质子运输到介观水平的研究DNA通过纳米孔。我们的主要兴趣是如何将孔/蛋白质结构与一些模型系统中的特定转运功能联系起来，这些模型系统从质子通道中的离子/质子转运到二级转运蛋白的溶质控制动力学，再到DNA和代谢物通过生物和人工纳米孔。拟议的研究将允许前瞻性地结合尖端模拟数据和实验研究，结合生物光谱学、中子衍射研究、固态NMR和电生理学。

The main theme of the proposed research program is the development and application of modern modelling approaches to understanding of solute transport in membrane proteins and nanopores. There are many sophisticated experimental methods to measure aspects of the behavior, shape, and interactions of molecules with nanopores and membrane proteins. Molecular machinery controlling specific ion and solute transport is the major component of cell-regulatory systems, which defines delivery routes for nutrients and osmolytes, cell signaling and generation of biological electricity. The trans-membrane proteins define remarkable mechanical and electrical properties of biological membranes, displaying surprisingly complex physical behavior and selectivity (ability to sort solutes) at or near diffusion limits. The dynamics of transport proteins is intimately coupled, via yet unknown mechanisms, to the specific cargo they are moving across the cell membranes. The various membrane proteins were used in the past in direct biotechnology applications and as templates for bio-inspired materials (proton nanowires for example). The size of the system and multiple confounding factors of the complex cellular environment represent substantial challenges interpreting molecular mechanisms of solute transport from experimental observations alone. Using powerful computers and a description of how atoms interact with each other, it is possible to calculate in atomic detail how biomolecules move and interact in time. This research project is aimed at developing and applying computational models of molecules to better understand the thermodynamics and kinetics of solute transport in narrow and wide biological pores. We have made significant progress in developing theories and methods for effective sampling of free energy surfaces, as well as developing methods for direct modelling and interpretations of experimental data on nanopores. We are in a unique position to study transport processes at various levels of resolution from electronic degrees of freedom relevant to proton transport to mesoscopic-level studies of DNA passage through a nanopore. Our main interest is how to relate pore/protein structure to specific transport function in a number of model systems spanning from ion/proton transport in proton channels to solute-controlled dynamics of secondary transporters to DNA and metabolite passage through biological and artificial nanopores. The proposed studies will allow a prospective combination of cutting-edge simulation data and experimental studies combining biological spectroscopy, neutron diffraction studies, solid-state NMR and electrophysiology.**