Insight into the degradation of type-I collagen fibrils by MMP-8.

Although a number of studies have shed light on the mechanism of collagen degradation in solution, the precise mechanism of collagenolysis in the native fibrillar state remains unclear. To gain insight into the mechanism of fibrillar degradation, we calculated the conformational free-energy landscape for unfolding regions of the α2 chain of type-I collagen within the context of the microfibril. Our data suggest that, relatively, imino-rich sequences maintain the canonical triple-helical structure at body temperature. By contrast, the unique MMP (matrix metalloproteinase) cleavage site adopts conformations where the α2 chain is dissociated from the rest of the fibril--behavior that is similar to what was observed in unfolding simulations of isolated collagen-like model peptides in solution. However, the dissociated cleavage site does not fit within the catalytic site of MMP-8, a representative fibrillar collagenase. Additional free-energy simulations suggest that the presence of the catalytic domain leads to a reorientation of the α2 chain such that it adopts a pose that is complementary to the enzyme's active site. These observations argue that, in the fibrillar state, there is a synergy between the normal thermal fluctuations of the substrate when the enzyme is absent and the fluctuations of the substrate when the enzyme is present. More precisely, our findings suggest that thermal fluctuations serve as the driving force for a degradative process that requires both an unfolded cleavage site and the presence of the enzyme.