Progress in Simulation Studies of Insulin Structure and Function

Abstract

Insulin is a peptide hormone known for chiefly regulating glucose level in blood among several other metabolic processes. Insulin remains the most effective drug for treating diabetes mellitus. Insulin is synthesized in the pancreatic β-cells where it exists in a compact hexameric architecture although its biologically active form is monomeric. Insulin exhibits a sequence of conformational variations during the transition from the hexamer state to its biologically-active monomer state. The structural transitions and the mechanism of action of insulin have been investigated using several experimental and computational methods. This review primarily highlights the contributions of molecular dynamics (MD) simulations in elucidating the atomic-level details of conformational dynamics in insulin, where the structure of the hormone has been probed as a monomer, dimer, and hexamer. The effect of solvent, pH, temperature, and pressure have been probed at the microscopic scale. Given the focus of this review on the structure of the hormone, simulation studies involving interactions between the hormone and its receptor are only briefly highlighted, and studies on other related peptides (e.g., insulin-like growth factors) are not discussed. However, the review highlights conformational dynamics underlying the activities of reported insulin analogs and mimetics. The future prospects for computational methods in developing promising synthetic insulin analogs are also briefly highlighted.

Computational Approach to Elucidating Insulin–Protamine Binding Interactions and Dynamics in Insulin NPH Formulations

“…The RMSD values less than 4 Å (Figure 6a) for all docked complexes are found to be consistent with the earlier reported literature. 22 Therefore, the docked complexes remain relatively stable and do not significantly deviate from the starting structure across the simulation run. A comparison of the RMSD values of the four docked complexes is shown in Figure 6a.…”

“…In this study, we used computational techniques to investigate the binding. Computational approaches, particularly molecular dynamics simulation, have proven to be quite useful in highlighting various aspects of insulin’s structure and function and have been widely used in the past . To begin, we used the molecular docking technique to map the precise binding sites and mode of binding of protamine to insulin.…”

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

“…Using bioinformatics tools and docking programs it is possible to search for promising inhibitors of insulin amyloid formation and its analogues. Some researchers pay special attention to computational methods, in particular, molecular dynamics, noting their importance for elucidating the mechanism of amyloid formation, as well as creating new insulin analogues [ 97 ]. Based on a theoretical analysis, it is necessary to select and synthesize peptide inhibitors of the amyloid formation of insulin and its analogues.…”

Structural models of viral insulin‐like peptides and their analogs

“…The binding of these peptides to their cognate receptors regulates key biological processes implicated in glucose homeostasis and cellular growth. [1][2][3][4][5][6][7][8][9][10][11][12] While Ins is a dual-chain (dc) peptide, consisting of an A-chain (21 residues) and a B-chain (30 residues) linked by three disulfide bonds, IGF1 is a single chain (sc) peptide with 70 residues, among which the residues 1-29, 30-41, 42-62, and 63-70 correspond to the B-, C-, A-, and D-domains, respectively. Ins modulates several physiological processes but is primarily responsible for maintaining the glucose level in blood.…”

“…Insulin (Ins) and insulin‐like growth factor‐1 (IGF1) are cognate peptides for the insulin receptor (IR) and the insulin‐like growth factor‐1 receptor (IGF1R), respectively. The binding of these peptides to their cognate receptors regulates key biological processes implicated in glucose homeostasis and cellular growth 1–12 . While Ins is a dual‐chain (dc) peptide, consisting of an A‐chain (21 residues) and a B‐chain (30 residues) linked by three disulfide bonds, IGF1 is a single chain (sc) peptide with 70 residues, among which the residues 1–29, 30–41, 42–62, and 63‐70 correspond to the B‐, C‐, A‐, and D‐domains, respectively.…”