Collaborative Research: Multi-Scale Modeling and Numerical Methods for Charge Transport in Ion Channels

生物学中的系统是遗传的，所有的信息都存在于基因中，即DNA中的核苷酸序列。这些基因产生蛋白质。分子和细胞生物学家已经非常详细地鉴定和分析了这些蛋白质：结构生物学家现在知道超过10万种蛋白质的单个原子的位置。位点诱变每天都在成千上万的实验室中进行，以改变生物功能。生物学的一个核心挑战是，当生物结构比原子大1000万倍，运动速度只有原子的万亿分之一时，理解原子是如何控制生物功能的。离子通道，本研究的主题，是这类系统的好例子。它们促进离子通过细胞膜的运输，并控制许多生物过程，包括细胞间通讯、信号传导、肌肉收缩等。在离子传输过程中，静电相互作用、离子相关性和尺寸效应都是理解通道选择性、电导率和其他关键行为的重要因素。离子通道在包括心脏和神经在内的几乎所有生物系统中起着至关重要的作用。大约13%的已知药物的主要治疗作用是针对离子通道的。该项目开发的方法将推动离子通道研究领域的发展，这将对酶催化、蛋白质工程、合理药物设计、药物传递以及新的诊断和治疗策略的研究产生影响。在本提案中，pi将发展多尺度数学理论和数值方法来研究涉及尺度差异的离子通道动力学的多物理场问题。重点研究的任务包括：a)建立基于反应场的静电相互作用混合溶剂化模型，以及考虑层状膜和溶剂环境的离子通道全原子MD模拟的多步加速动力学集成方法；b)开发新的改进的PNP连续体模型和新的数值方法来解决离子通道中拥挤离子效应和离子种类之间的相对阻力；c)对新的PNP模型进行数学分析和物理理解；d)基于多尺度静电溶剂化MD和PNP模型的模拟。在高中、本科和研究生阶段的教育工作将是这个项目的一个组成部分，这个项目的研究成果将被纳入两个参与机构的应用/计算数学课程。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Systems in biology are inherited, with all the information being in genes that are sequences of nucleotides in DNA. These genes produce proteins. Molecular and cell biologists have identified and analyzed these proteins in great detail: structural biologists now know the position of individual atoms of more than a hundred thousand proteins. Site-directed mutagenesis is done in thousands of laboratories every day to change biological function. A central challenge in biology is to understand how the atoms control biological function when biological structures are some 10 million times larger than atoms and move at a ten thousand billionth of their speed. Ion channels, the subject of this research, are good examples of such systems. They facilitate the transport of ions through cell membranes and control many biological processes, including cell-cell communication, signaling, muscle contraction etc. During ion transport, electrostatic interactions and ion correlation and size effects are all important factors to understand the channel selectivity, conductance, and other critical behaviors. Ion channels play critical roles in almost all biological systems including heart and nerves. About 13% of known drugs have their primary therapeutic actions targeted at ion channels. The methods developed in this project will advance the field of ion channel research, which will have an impact on research on enzyme catalysis, protein engineering, rational drug design, drug delivery, and new diagnostic and therapeutic strategies. In this proposal, the PIs will develop multiscale mathematical theories and numerical methods to study the multi-physics problems related to the ion channel dynamics involving a disparity of scales. The tasks to be focused on include a) developing a reaction field based hybrid solvation model for electrostatic interactions, and multi-step accelerated dynamics integration methods for all-atom MD simulations of ion channels, accounting for layered membrane and solvent environments; b) developing new improved PNP continuum models and new numerical methods to address crowded ions effects and relative drags between ion species in ion channels; c) pursuing mathematical analysis and physical understanding of the new PNP models; d) simulations based on the multi-scale electrostatic solvation MD and the PNP models. Educational efforts at high school, undergraduate, and graduate level will be an integrated part of this project, and research results from this project will be incorporated into the applied/computational mathematics curriculum at the two participating institutions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.