title: Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.
abstract: A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C-terminal (BC-CT) as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1) The opening of the BC-CT is inherently stochastic and progresses through an open and then a "wide-open" conformation--the wide-open conformation is essential for receptor binding, but occurs only rarely. 2) The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin) is initiated. 3) The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation.
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.|School of Physics, University of Sydney, Sydney, NSW, Australia.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Papaioannou
authors.affiliation: School of Physics, University of Sydney, Sydney, NSW, Australia.
authors.forename: Serdar
authors.initials: S
authors.lastname: Kuyucak
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.|School of Physics, University of Sydney, Sydney, NSW, Australia.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Kuncic
mesh_terms: D001665:Binding Sites / Q000235:genetics*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics*; D011487:Protein Conformation; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D007328:Insulin; D011972:Receptor, Insulin