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

拟议研究计划的主要主题是开发和应用现代模拟方法，以了解膜蛋白和纳米孔中的溶质运输。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。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，它定义了营养物质和渗透调节物质的传递途径、细胞信号传递和生物电的产生。跨膜蛋白定义了生物膜显著的机械和电学性质，在扩散极限或接近扩散极限时显示出令人惊讶的复杂的物理行为和选择性(对溶质进行分类的能力)。运输蛋白的动态通过尚不清楚的机制与它们在细胞膜上移动的特定货物紧密耦合。过去，各种膜蛋白被直接用于生物技术应用，也被用作仿生材料(例如质子纳米线)的模板。该系统的规模和复杂细胞环境的多个混杂因素构成了仅从实验观察来解释溶质运输的分子机制的巨大挑战。使用强大的计算机和对原子如何相互作用的描述，可以详细计算生物分子如何在时间上移动和相互作用。这一研究项目旨在开发和应用分子计算模型，以更好地了解生物狭孔和宽孔中溶质运移的热力学和动力学。我们在开发有效采样自由能表面的理论和方法以及开发直接模拟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来研究不同分辨率水平的传输过程，从与质子传输相关的电子自由度到DNA通过纳米孔的介观水平的研究。我们的主要兴趣是如何在许多模型系统中将孔/蛋白质结构与特定的运输功能联系起来，从质子通道中的离子/质子运输到溶质控制的二级转运体到DNA的动力学以及通过生物和人工纳米孔的代谢物通道。拟议的研究将允许将尖端模拟数据与实验研究相结合，结合生物光谱学、中子衍射研究、固态核磁共振和电生理学。

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.