Do collagenases unwind triple-helical collagen before peptide bond hydrolysis? Reinterpreting experimental...

It has been postulated that triple-helical collagen is actively unwound by collagenases before peptide bond hydrolysis--a supposition that explains the small catalytic rate constant associated with collagenolysis. We propose an alternate model of collagen degradation that does not require active unwinding by collagenases, but instead suggests that the regions of collagen near the collagenase cleavage site can adopt either a native triple-helical or a partially unfolded conformation. In this model, collagenases preferentially bind to and stabilize partially unfolded conformers before cleaving the scissile bond. Existing experimental observations (which were previously taken to support active unwinding models) are reinterpreted using corroborative evidence from numerical simulations and found to be consistent with this framework. These data support the notion that collagen, like all other biological heteropolymers, undergoes thermal fluctuations that cause it to sample distinct structures in the neighborhood of the native state, and collagenolysis occurs when collagenases recognize the appropriate unwound conformers.