Osteogenesis imperfecta mutations lead to local tropocollagen unfolding and disruption of H-bond network

Abstract

Osteogenesis imperfecta (OI), also known as “brittle bone disease”, is a rare genetic disorder of collagen tissues characterized by brittle bones and, in severe cases, prenatal death. Even though the macroscale consequences of the disease are well known, the effects of the mutations on the folding of collagen triple helix remain largely unknown. In this work we carry out metadynamics molecular simulations to estimate the effects of OI mutations on the folding of collagen triple helix, by quantifying the free energy changes as a function of the interchain distance, for all seven glycine substitutions known to lead to OI. We find that OI mutations lead to significant local unfolding in the vicinity of the mutation and that this phenomenon is more pronounced for mutations associated with the most severe OI phenotypes. We show that the mutation-induced unfolding leads to the disruption of the local interchain H-bonds, but the extent of the disruption is independent of the mutation type. We discuss our findings in the context of the three main OI mechanism models proposed in the literature, showing that the findings described here fit well in these models and, more importantly, could provide an important step towards a unified picture of OI aetiology.