Methods of theoretical conformational computations will be applied to collagen, in order to analyze and interpret the interactions that determine its molecular structure and the hierarchical supramolecular self-organization.
The aim of this study is an understanding of the physical and chemical factors, especially noncovalent interactions, that determine the structure of the collagen molecule and of its fibrillar aggregates and influence their stability. Physical and chemical properties, as well as the resistance of collagen to degradation, depend on these interactions. The chemical and mechanical behavior of collagen is altered in aging, but little is known about the mechanisms involved. Abnormal behavior of collagen in several age-related diseases has been attributed to modifications of molecular stability, fibril packing, and crosslinking. The purpose of this research is to elucidate the structural basis for the properties of normal collagen and for the altered properties connected with aging and with connective tissue diseases' in order to aid the understanding of the chemical and physiological events that lead to abnormal behavior in aged or diseased tissues. The energetics of packing and alignment of triple-helical type I and III collagen molecules will be studied as a function of amino acid sequence and hydration, in order to derive a model for fibrillogenesis. The structural effects of amino acid substitu- tions or deletions in genetic diseases of collagen will be assessed. Computations of the energy and entropy of the helix-coil conversion will be used to estimate the rigidity of the triple helix, with special attention to the possibility of sequence- dependent local destabilization, in relation to the susceptibility to enzymatic degradation. The properties of proline analogs. useful in preventing fibrosis, will be correlated with their destabilizing effect on the triple helix. The conformations of the nonhelical telopeptides of collagen and their relationship with constraints governing crosslinking will be analyzed, in order to describe the effect of changed crosslinking in aging and in age- related diseases on the chemical and mechanical properties of collagen.
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