Elucidating the Mechanism of Collagenolysis in the Native Collagen Fibril

Abstract

Collagen is an important structural biomolecule that is abundant in all animals. Proper degradation and remodeling of collagen is crucial to an organism's survival; moreover, excessive degradation of collagen is involved in many disease processes such as atherosclerosis, cancer metastasis, and arthritis. While a number of studies have shed light on the mechanism of collagenolysis in solution, the precise mechanism of collagen degradation in the native fiber remains mysterious. In this work, we use molecular dynamics simulations on a model of native collagen fibrils, obtained from recent fiber diffraction data, to understand the mechanism of fibrillar degradation. Our data suggest that the unique collagenase cleavage site in native fibrillar state behaves much like it does in solutions composed of tropocollagen molecules. In particular, in the fibrillar state the region about the collagenase cleavage site can adopt two distinct conformational states - one where the atoms comprising the scissile bond are relatively hidden and another state where the scissile bond is relatively exposed, or vulnerable, to collagenolysis. These data extends our previous work and suggests that conformational flexibility plays an important role in determining the rate of collagenolysis in collagen fibrils.