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

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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.