Diabetes mellitus caused by mutations in human insulin: analysis of impaired receptor binding of insulinsWakayama,Los AngelesandChicagousing pharmacoinformatics

Abstract

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 positions B24 and B25 is replaced by serine and leucine, respectively. These mutations show radical changes in binding affinity for IR. The ZDOCK server was used for molecular docking, while AMBER 14 was used for the MD study. The published crystal structure of IR bound to natural insulin was also used for MD. The binding interactions and MD trajectories clearly explained the critical factors for deprived binding to the IR. The surface area around position A3 was increased when valine was substituted by leucine, while at positions 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 IR that leads to instability of the complex. In the MD simulation, the normal mode analysis, 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.

Water models for biomolecular simulations

“…The GB model is widely used in all kinds of atomistic simulations: some examples of the GB model usage include studies of protein folding and design, modeling of ‘large scale’ motions in biomolecules, estimates of solvation energies of small molecules, analysis of nucleic acid conformational energetics, binding between proteins and nucleic acids, modeling of peptides in membrane environment, constant pH MD, studies of protein–ligand binding, use in docking programs such as DOCK, and many others . In a recent landmark study, folding simulations of 17 proteins (many of which were used in the earlier explicit solvent study mentioned above) were performed on a commodity PC within days .…”

Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26

“…Long MD simulations are necessary for sufficient sampling to validate the calculations as shown in this study, where the analogues were run for 600–1200 ns. In a recent computational study, binding of the hyperinsulinemia analogues to the insulin receptor was analyzed [53] . The analogues were docked to the IR using computational docking tools.…”

“…Although a significant number of experimental studies focus on insulin and its complex structure with the IR [16] , [17] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [31] , [32] , [33] , [46] , [47] , [48] , [49] , [50] , as well as on mutations on the critical residues of insulin for predicting potential therapeutic candidates [23] , [25] , [26] , [27] , [31] , [46] , [47] , [48] , [49] , there are still a lot of key features that cannot be solved or are hard to explain using only experimental approaches. There have been relatively few computational studies investigating the conformational changes and dynamics of insulin [25] , [30] , [31] , [51] , [52] , and even less focusing on insulin mutations [25] , [31] , [53] , [54] . Therefore, we present a comprehensive computational study of mutant insulins, focusing on changes in the activity, dynamics, energetics and conformations of insulin due to mutations using molecular dynamics (MD) simulations.…”

A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease

“…Like several other mutations that affect residues involved in receptor binding, substitutions at B24 also invariably impact stability as the hydrophobic phenylalanine serves as a stabiliser of the core helical structure. p.F48S; ( B24 ) (insulin Los Angeles) [ 6 , 101 ] and p.F49L; ( B25 ) (insulin Chicago) lead to dramatically reduced receptor binding, and these mutant insulins have a prolonged half-life [ 8 , 26 , 102 , 103 , 104 , 105 ].…”