Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.

Anastasios Papaioannou,Zdenka Kuncic,Serdar Kuyucak,Anthony M George

doi:10.1371/journal.pone.0144058

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.

Highlights

Insulin is a polypeptide hormone that plays a crucial role in regulating glucose levels in higher organisms
The dynamics of how insulin binds to the insulin receptor (IR) and activates signal transduction needs to be better understood for pharmacological applications
Our simulation results have revealed for the first time that the activation of insulin is stochastic in nature, with no obvious deterministic behavior

Summary

Introduction

Insulin is a polypeptide hormone that plays a crucial role in regulating glucose levels in higher organisms. Defects in insulin signalling can lead to insulin resistance, which is the hallmark of diabetes mellitus. The key molecular mechanisms and kinetics in the insulin-signaling pathway have been extensively studied but a complete picture is yet to emerge. The dynamics of how insulin binds to the insulin receptor (IR) and activates signal transduction needs to be better understood for pharmacological applications. Insulin comprises two polypeptide chains, a 21 amino acid A-chain made of two α-helices, and a 30 amino acid B-chain containing a central α-helix (see Fig 1A). The two chains are constrained by two inter-chain (A7–B7 and A20–B19) and one intra-chain (A6–A11) disulphide bridges (see Fig 1B). The first crystal structure of insulin was determined by Adams et al in 1969 [1] followed by other structures of insulin and its analogs in the storage form (hexamers and dimers) [2,3].

Methods

Results

Conclusion