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。我们的目标是了解VDAC静电学和动力学如何改变物种跨外线粒体膜的运输，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、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。离子通道模型和数值算法可应用于其他涉及物种输运、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的教育和研究机会。电压依赖性阴离子通道(VDAC)是线粒体外膜(OMM)上含量最丰富的蛋白质，是离子物质(离子和代谢产物)同时进入和离开线粒体的主要通道。通过VDAC通过OMM运输物种的改变可以影响线粒体功能，从而导致疾病病理。然而，目前的线粒体模型不能解释物种通过VDAC通过OMM的传输，并且目前的离子通道模型都不适用于OMM上的VDAC，在许多不同离子大小的离子物种的混合物中。这个项目将通过一种综合的方法来解决这些重要问题，该方法结合了最先进的数学建模和计算方法来研究VDAC和线粒体功能。该项目旨在开发一个非局域Poisson-Nernst-Planck-Fermi(NPNPF)离子通道模型，该模型将适用于VDAC中具有不同离子大小的许多离子物种的混合物。一个主要的目标是开发有效的NPNPF有限元求解器(算法和软件程序)和计算离子通道动力学(吉布斯自由能、膜电位、电化学势、电流和传输通量)的数值方案。另一个主要目的是将所得到的离子通道动力学应用于开发一个新的VDAC-线粒体集成模型，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。NPF和VDAC-线粒体模型都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微观VDAC静电学和宏观VDAC动力学与线粒体功能之间的潜在分子机制的模型。这一结果有望改变人们对VDAC静电学和动力学如何有助于线粒体疾病发病机制的理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.