Interfacial and osmolyte-induced modulation of protein folding, assembly and adhesion

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Proteins are fundamental building blocks of life, serving a multitude of functions in our body, from antibodies protecting us from infection, to enzymes catalyzing biochemical reactions. Protein function is intimately tied to the conformations (or shapes) that proteins can adopt. This project seeks to develop new computational tools to probe how surfaces and solution conditions affect protein structure and function. These simulations will guide the design of a new class of proteins for biomaterial applications, including biologically-inspired wet adhesives and protein scaffolds. Codes developed in the context of this project will be made freely available. The PI and her group are actively engaged in outreach activities, including a chemistry program geared at 5th grade students, the development of hands-on modules related to wet-adhesion that will be presented at the Santa Barbara zoo, and the involvement of underrepresented minority high school students in a summer research program.The focus of this project is on intrinsically disordered peptides, a class of proteins that can take on a multitude of disparate conformations, adopt transient secondary structures, and carry out multiple functions. With their lack of a native fold, they are also prone to self-assemble into structures ranging from fibrils to coacervates. In this project, the structure, function and assembly of model intrinsically disordered peptides will be probed using a hierarchy of simulations techniques, from ab initio molecular dynamics to coarse-grained models. The project will address three specific aims. The first aim will focus on a molecular understanding of wet adhesion, using the intrinsically disordered mussel-foot protein as a model system. Working closely with leading experimental groups in the field of biological adhesion, the PI will investigate how sequence and surface composition affect adhesion. This research will lay the groundwork for the development of a new class of biologically inspired peptides that can serve as underwater adhesives. In a second aim, the PI will use molecular dynamics simulations and the Kirkwood-Buff theory of solutions to determine the mechanism by which the osmolyte TMAO counteracts the protein denaturing effects of the osmolyte urea. An optimized force field for TMAO/urea interactions will be developed and validated based on experimental measurements, and used to study the effects of mixed osmolytes on the aggregation of intrinsically disordered peptides. In a third aim, the PI will develop novel hybrid kinetic Monte Carlo/Molecular Dynamics algorithms that will be applied to the study of fibril elongation.This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.