Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at position B24 and B25 are replaced by serine and leucine respectively. These
mutations show radical changes in binding affinity for insulin receptor. The ZDOCK server was used for molecular docking while AMBER 14 was used for the molecular dynamics study. The published crystal structure of insulin receptor bound to natural insulin was also used for molecular dynamics. The binding interactions and molecular dynamics trajectories clearly explained the critical factors for deprived binding to the insulin receptor. The surface area around position A3 was increased when valine was substituted by leucine, while at
position B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of insulin receptor that leads to instability of the complex. In the MD simulation the normal mode analysis (NMA), rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin < insulin Chicago < insulin Los Angeles < insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR.