Type I collagen is a fibrous protein which is commonly used in the human body for structural and functional integrity. Mutations in the alpha-1 and alpha-2 chains of this triple-helical protein induce the disease Osteogenesis Imperfecta (OI). OI is expressed in people by a number of phenotypes ranging from a disease process that is lethal in utero to one that is only detected through gene analysis. We are using the techniques of molecular dynamics and free energy perturbation to predict the phenotypic severity that result from single point mutations of type I collagen. In particular, we are focusing on the following three issues in our investigation: 1) validation of the AMBER molecular mechanics force field for studying fibrous proteins; 2) determination of protein and water-protein structural changes induced by single point mutations of type I collagen; 3) determination of changes in stability between native collagen fragments and collagen fragments in which a single point mutation has occurred. We have completed the validation of the AMBER molecular mechanics force field for both molecular dynamics and free energy perturbations of collagen-like peptides. We have determined that solvent provides an overall network of stability to the collagen molecule, but does not provide the inherent stability to the triple helix. We have begun a collaboration with Professor Ron Raines at the University of Wisconsin to determine what molecular interactions/effects (e.g., hydrogen bonding, induction effects) contribute to the stability of the triple helix.
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