This project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry, the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Computational and Data-Enabled Science and Engineering program.
The Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Charles L. Brooks III from the University of Michigan to develop computational methods to explore protein-protein interactions. Protein-protein interactions (PPIs) form the basis for most biological processes. An atomic description of the key features of protein-protein interactions will yield tremendous benefits in both establishing a fundamental understanding of the processes that support all living systems, and gaining the ability to manipulate and control those processes. Experimental approaches such as nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography can reveal features of interacting complexes and isolated monomers of key protein-protein interactions, but have difficulty capturing dynamic, flexible systems. Molecular dynamics (MD) is a useful tool to deconvolute these experimental measurements, and offers a detailed, dynamic view of molecular interactions. Although brute force MD approaches have made significant progress studying the dynamics of single molecule systems, they have fundamental difficulties with biologically relevant PPIs due to the large sizes, long time scales and high flexibility of these systems. This project will develop, test and apply computational approaches that enable MD studies to probe the interactions of the viral capsid glycoprotein Hemagglutinin with putative human antibody mimics, and the chaperone activity of the bacterial acid-shock chaperone HdeA. Dr. Brooks will provide training for a postdoc, graduate student and a number of undergraduates as well as mentoring them in the development of physical theories and simulation methods to study protein-protein interactions. Moreover, the findings, methods and techniques developed in this project will be distributed through tutorials and case studies to be integrated into the Multiscale Modeling Tools for Structural Biology (MMTSB) tutorials as well as into courses taught at the University of Michigan
The specific outcome of the project will be computational tools and methods to i) predict environment-dependent NMR observables from coarse-grained (CG) simulations; ii) undertake the development of transferable CG interaction potentials that are specially designed for reproducing observed protein-protein interfaces; iii) undertake the development of enhanced sampling methods for efficient determination of thermodynamic and kinetic properties of intermolecular interactions. The work will focus on two demanding benchmark cases: the interactions of the viral capsid glycoprotein Hemagglutinin with putative human antibody mimics, and the chaperone activity of the bacterial acid-shock chaperone HdeA. The former system is difficult due to the large system size (>600 amino acids total), while the interactions in the latter system are highly dynamic, sensitive to the system pH, and involve multiple copies of HdeA and substrate protein.
