title: Molecular and mesoscale mechanisms of osteogenesis imperfecta disease in collagen fibrils.
abstract: Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases.
authors: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Alfonso
authors: A
authors: Gautieri
authors: Sebastien
authors: S
authors: Uzel
authors: Simone
authors: S
authors: Vesentini
authors: Alberto
authors: A
authors: Redaelli
authors: Markus J
authors: MJ
authors: Buehler
mesh_terms: D003198:Computer Simulation; D055119:Elastic Modulus; D004548:Elasticity; D024022:Fibrillar Collagens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005998:Glycine; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D011336:Probability; D055672:Static Electricity; D014332:Tropocollagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D024022:Fibrillar Collagens; D014332:Tropocollagen; D005998:Glycine