title: Diabetes mellitus caused by mutations in human insulin: analysis of impaired receptor binding of insulins Wakayama, Los Angeles and Chicago using 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.
authors.affiliation: a Faculty of Health Sciences, Department of Chemical Pathology , & Institute of Cellular & Molecular Medicine, University of Pretoria and National Health Laboratory Service Tshwane Academic Division , Pretoria , South Africa.
authors.forename: Md Ataul
authors.initials: MA
authors.lastname: Islam
authors.affiliation: b Department of Chemical Technology , University of Calcutta , 92, A. P. C. Road, Kolkata 700009 , India.
authors.forename: Sagar
authors.initials: S
authors.lastname: Bhayye
authors.affiliation: c Discipline of Pharmaceutical Sciences , School of Health Sciences, University of KwaZulu-Natal , Durban 4000 , South Africa.
authors.forename: Adebayo A
authors.initials: AA
authors.lastname: Adeniyi
authors.affiliation: c Discipline of Pharmaceutical Sciences , School of Health Sciences, University of KwaZulu-Natal , Durban 4000 , South Africa.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
authors.affiliation: a Faculty of Health Sciences, Department of Chemical Pathology , & Institute of Cellular & Molecular Medicine, University of Pretoria and National Health Laboratory Service Tshwane Academic Division , Pretoria , South Africa.|d Division of Chemical Pathology , University of Cape Town , Cape Town , South Africa.
authors.forename: Tahir S
authors.initials: TS
authors.lastname: Pillay
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D002641:Chicago; D003920:Diabetes Mellitus / Q000209:etiology*; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007564:Japan; D015141:Los Angeles; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D011972:Receptor, Insulin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D015703:Antigens, CD; D007328:Insulin; D050505:Mutant Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin
keywords: ZDOCK; insulin; insulin receptor; molecular dynamics; protein–protein docking