We have carried out stochastic boundary molecular dynamics simulations to estimate free energy changes for substitutions of Gly with Val, Arg and Trp residues in a collagen-like peptide. The relative free energy change differences of mutants containing a Val, an Arg and a Trp relative to the wild type are 5.7, 8.1 and 9.5 kcal/mol, respectively. The corresponding free energy change differences of mutants containing two mutated residues are on average 7.6, 10.5 and 14.7 kcal/mol, respectively. We show that the free energy change differences are correlated with the severity of OI from statistical analysis and mechanical properties of the individual tropocollagen molecules. This simulation result indicates an atomistic-level mechanistic understanding of the effect of OI mutations in terms of stability of the mutants relative to the wild type, which could eventually provide a new strategy for diagnosis and treatment of the disease.
- Free energy simulation
- Osteogenesis imperfecta
- Stochastic boundary molecular dynamics
- Thermodynamic integration