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

膜蛋白和人造纳米孔中溶质和离子传输的多尺度模型

• 批准号: RGPIN-2016-03848
• 负责人: Noskov, Sergei
• 金额: $ 4.44万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632378
• 关键词: Multi; scale; models; solute; ion

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.

拟议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可以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器是细胞调节系统的主要组成部分，它定义了营养物和渗透剂的输送途径、细胞信号传导和生物电的产生。跨膜蛋白定义了生物膜显着的机械和电学特性，在扩散极限或接近扩散极限时表现出令人惊讶的复杂物理行为和选择性（对溶质进行分类的能力）。转运蛋白的动力学通过未知的机制与它们跨细胞膜移动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，并作为仿生材料（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对仅从实验观察中解释溶质转运的分子机制提出了巨大的挑战。使用功能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及时移动和相互作用。该研究项目旨在开发和应用分子计算模型，以更好地了解狭窄和宽生物孔中溶质运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纳米孔实验数据的直接建模和解释方法方面取得了重大进展。我们处于独特的地位，可以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研究。我们的主要兴趣是如何将孔/蛋白质结构与许多模型系统中的特定转运功能联系起来，从质子通道中的离子/质子转运到二次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的通道。拟议的研究将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、固态核磁共振和电生理学。