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Osteogenesis imperfecta mutations lead to local tropocollagen unfolding and disruption of H-bond network
| Content Provider | Semantic Scholar |
|---|---|
| Author | Gautieri, Alfonso Vesentini, Simone Redaelli, Alberto Buehler, Markus J. |
| Copyright Year | 2012 |
| 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://web.mit.edu/mbuehler//OldFiles/www/papers/RSC_Advances_2012.pdf |
| Alternate Webpage(s) | http://web.mit.edu/mbuehler/www/papers/RSC_Advances_2012.pdf |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Amino Acids Body tissue Bone Diseases Cessation of life Consortium Cost per mille Denial-of-service attack Glycine Gradient Hereditary Diseases Holism IBM Notes Lobstein's Disease Metadynamics Molecular modelling Mutation Nephrogenic Systemic Fibrosis Onset (audio) Opportunistic Infections Osteogenesis Imperfecta Phenotype Simulation Skeletal bone Steam rupture Tropocollagen Unfolding (DSP implementation) Unified Model Zipper explanation free energy |
| Content Type | Text |
| Resource Type | Article |
