title: Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown.
abstract: Collagen cleavage, facilitated by collagenases of the matrix metalloproteinase (MMP) family, is crucial for many physiological and pathological processes such as wound healing, tissue remodeling, cancer invasion and organ morphogenesis. Earlier work has shown that mechanical force alters the cleavage rate of collagen. However, experimental results yielded conflicting data on whether applying force accelerates or slows down the degradation rate. Here we explain these discrepancies and propose a molecular mechanism by which mechanical force might change the rate of collagen cleavage. We find that a type I collagen heterotrimer is unfolded in its equilibrium state and loses its triple helical structure at the cleavage site without applied force, possibly enhancing enzymatic breakdown as each chain is exposed and can directly undergo hydrolysis. Under application of force, the naturally unfolded region refolds into a triple helical structure, potentially protecting the molecule against enzymatic breakdown. In contrast, a type I collagen homotrimer retains a triple helical structure even without applied force, making it more resistant to enzyme cleavage. In the case of the homotrimer, the application of force may directly lead to molecular unwinding, resulting in a destabilization of the molecule under increased mechanical loading. Our study explains the molecular mechanism by which force may regulate the formation and breakdown of collagenous tissue.
authors.affiliation: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Chang
authors.forename: Brendan P
authors.initials: BP
authors.lastname: Flynn
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Ruberti
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Buehler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D055550:Protein Stability; D013314:Stress, Mechanical
chemical_list: D003094:Collagen; D017364:Collagenases