DMS/NIGMS 1: Collaborative Research: Advanced Ion Channel Modeling and Computational Tools with Application to Voltage-Dependent Anion Channel and Mitochondrial Model Development

本项目研究线粒体外膜上的电压依赖性阴离子通道（VDAC）在调节线粒体关键功能中的作用。目标是了解VDAC静电和动力学如何改变物种在线粒体外膜上的运输，以及这反过来如何影响关键的线粒体功能。该项目的主要成果将是最先进的数学模型、数值算法和软件工具。计算机模拟将为确定心血管和其他疾病的潜在治疗靶点提供基础。数值算法将对生物物理学、生物化学、计算生物学和生物医学工程等领域做出重要贡献。离子通道建模和数值算法可以应用于其他涉及物质输运、多物理域和复杂界面的物理和工程系统。由此产生的软件工具可用于许多其他生物医学和生物工程应用。该项目还将为威斯康星州东南部的高中生、本科生和研究生提供多学科教育和研究机会。电压依赖性阴离子通道（VDAC）是线粒体外膜（OMM）上最丰富的蛋白质，是同时运输离子（离子和代谢物）进出线粒体的主要通道。通过VDAC改变OMM的物种运输可以影响导致疾病病理的线粒体功能。然而，目前的线粒体模型并没有考虑到通过VDAC在OMM中的物种运输，并且目前的离子通道模型都不能用于VDAC在OMM中混合许多不同离子大小的离子物种。该项目将通过结合最先进的数学建模和计算方法来研究VDAC和线粒体功能的综合方法来解决这些重要问题。该项目旨在开发一种非局部泊松-能内斯特-普朗克-费米（NPNPF）离子通道模型，该模型将在具有不同离子大小的许多离子种类的混合物中用于VDAC。一个主要目标是开发有效的NPNPF有限元求解器（算法和软件程序）和计算离子通道动力学的数值方案（吉布斯自由能、膜势、电化学势、电流和输运通量）。另一个主要目标是将离子通道动力学应用于开发一种新的集成VDAC-线粒体模型，以产生一个改进的模型，该模型反映了离子大小、原子电荷、VDAC分子结构和非局部介电性质的影响。NPNPF和vdac -线粒体模型将通过生化动力学数据进行验证。VDAC-线粒体模型将是第一个能够阐明将微观VDAC静电和宏观VDAC动力学与线粒体功能联系起来的潜在分子机制的模型。该结果有望改变对VDAC静电和动力学如何促进线粒体病发病机制的理解。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。

This project studies the role of the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane in regulating key mitochondrial functions. The goal is to understand how VDAC electrostatics and kinetics alter species transport across the outer mitochondrial membrane, and how that in turn impacts key mitochondrial functions. The major outcomes of this project will be state-of-the-art mathematical models, numerical algorithms, and software tools. The computer simulations will provide a basis for identifying potential therapeutic targets for cardiovascular and other diseases. The numerical algorithms will be important contributions to the fields of biophysics, biochemistry, computational biology, and biomedical engineering. The ion channel modeling and numerical algorithms can be applied to other physical and engineering systems that involve species transport, multiple physical domains, and complicated interfaces. The resulting software tools can be used for many other biomedical and bioengineering applications. This project will also provide multidisciplinary education and research opportunities to high school, undergraduate, and graduate students in Southeast Wisconsin. Voltage-dependent anion channel (VDAC) is the most abundant protein on the outer mitochondrial membrane (OMM) and is the main conduit for simultaneous transport of ionic species (ions and metabolites) into and out of a mitochondrion. Alteration of species transport across OMM via VDAC can impact mitochondrial functions leading to disease pathologies. However, current mitochondrial models do not account for species transport across OMM via VDAC, and none of the current ion channel models work for VDAC on OMM in a mixture of many ionic species of different ion sizes. This project will address these important issues via an integrative approach combining state-of-the-art mathematical modeling and computational methodologies to study VDAC and mitochondrial functions. The project aims to develop a nonlocal Poisson-Nernst-Planck-Fermi (NPNPF) ion channel model that will work for VDAC in a mixture of many ionic species with distinct ion sizes. One major aim is to develop effective NPNPF finite element solvers (algorithms and software programs) and numerical schemes for computing ion channel kinetics (Gibbs free energy, membrane potential, electrochemical potential, electric currents, and transport fluxes). The other major aim is to apply the resulting ion channel kinetics to the development of a novel integrated VDAC-mitochondrial model to yield an improved model that reflects the effects of ion sizes, atomic charges, VDAC molecular structures, and nonlocal dielectric properties. Both NPNPF and VDAC-mitochondrial models will be validated by biochemical kinetic data. The VDAC-mitochondrial model will be the first that can elucidate the underlying molecular mechanisms that link microscopic VDAC electrostatics and macroscopic VDAC kinetics to mitochondrial function. The results are expected to transform understanding of how VDAC electrostatics and kinetics contribute to the pathogenesis of mitochondriopathic diseases.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.