Multi-scale simulation methods for energy transduction and macromolecular assembly

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Qiang Cui, of the University of Wisconsin, is supported by an award from the Chemical Theory, Models and Computational Methods program to develop effective molecular simulation methodologies to tackle important and challenging biophysical and chemical problems that involve multiple length scales. The award is cofunded by the Biophysics Program in the Division of Molecular and Cellular Biology. Bioenergy transduction, a type of energy transport in which the form of the energy also changes, is one of the most fascinating aspects of life. Biomolecular motors and pumps transduce energy from one form to the other with remarkable efficiency. The study of energy transduction in biomolecular ion pumps involves developing quantum mechanical and classical models that properly describe the energetics and efficiency of ion transport through the interior of a transmembrane protein. The problem of macromolecular assembly, which underlies many fascinating biological processes such as the formation of muscle fiber, requires the development of effective coarse-grained models that strike the balance of computational efficiency and biophysical specificity. The project offers research opportunities for students at all levels who wish to work at the intersection of chemistry, biology and engineering. Dr. Cui is actively engaged with programs aimed at broadening participation in physical and biological science by members of under-represented minorities.For the problem of ion pumping, by adopting the minimum free energy path approach and a multi-layer Quantum Mechanics/Molecular Mechanics (QMMM) model, Cui and co-workers can significantly improve the accuracy and sampling for the study of long-range proton transfers in complex biomolecules compared to previous efforts. By adopting the chemical potential equalization scheme to represent the polarization of different QM regions, they can properly describe ion transport through the interior of a transmembrane protein that is rich in polar and charged motifs. This computational framework represents the first attempt to include the membrane potential in QM/MM type of simulations. For the problem of coiled-coil assembly, which describes a broad class of problems in which the proper assembly of biomolecules relies critically on a limited degree of flexibility in their structures, their proposed multipolar coarse-grained model makes a natural connection between atomistic and coarse-grained representations with a transparent framework for parameterization. Compared to continuum mechanics models, this model can access similar length and time scales but can be efficiently studied using standard molecular simulation software.