Collagen is a fibrous protein that provides structural and functional integrity in the human body. (See image above or download this high resolution TIFF image [7.6MB!].) Osteogenesis imperfecta (OI) is a genetic disorder of collagen which occurs when there are mutations in the triple helix. Currently, only the diagnosis of a lethal OI phenotype can be determined in utero. Diagnosis of other OI phenotypes cannot be made until after birth. Mutations in type I collagen lead to an array of minor to lethal disorders. An understanding of the physical properties of native and mutant collagens will provide the basis for comprehending the etiology of OI phenotypes at the molecular level. This information is critical for the ultimate development of more useful genetic counseling protocols. Our strategy involves the development and application of tools to study various physical and chemical properties of collagen molecule fragments in order to predict the effects of amino acid substitution on the stabilities of the collagen helical conformation.
We are using molecular dynamics and free energy of denaturation calculations to compute the energetic and structural consequences of single point mutations and correlate the magnitude of these changes with the experimentally observed data with the phenotypic severity of OI. By probing the problem at the molecular level, we will investigate structural changes that sufficiently alter the energetics and conformation of the triple helix to disrupt fibril formation. These structural consequences include the disruption of the collagen triple helix and the formation of alternate solvent/collagen interactions. From these computational studies, we will determine the correlations among the calculated quantities, experimentally determined melting temperature changes and OI mutation and neighborhood. Identification of relevant components in the free energy calculations will provide the foundation for a predictive energetic-structural model for a number of OI phenotypes and may provide an improved model for development of genetic counseling protocols.
Acknowledgments: This research is supported by the National Institutes of Health, grant AR41223 (P.H. Byers, P.I.), the University of California Office of the President, grant STAR S96-32 (T.E. Klein, P.I.), and the National Center for Research Resources, grant P41-RR01081 (T.E. Ferrin, P.I.). If you are interested in diagnostic testing for connective tissue diseases such as Osteogensis imperfecta, you might find the Univ. of Washington's Collagen Diagnostic Laboratory informative.
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