Molecular dynamics simulations to study pathogenic mutations in proteins

Here we present an example of application of molecular dynamics simulations, i.e. the study of pathogenic mutations in a protein, the FXI factor, that causes defects in blood coagulation. Starting from the measurement of the crystal structure of the protein, molecular dynamics simulations allow us to study changes in flexibility and movements of the mutated protein compared to the native form of the protein, and thus help to understand the molecular basis of disease. Molecular dynamics data have been extensively generated by using grid computing. This large amount of data has been analyzed by algorithms which capture structural features. In particular, the variations in the atomic distances between amino acids and in their exposure to the solvent , the formation or breaking of hydrogen bonds, and the distributions of the backbone dihedral angles, were calculated. Thus insights into the molecular basis of pathogenesis for each mutation found in population were obtained.