Activation of human insulin by vitamin E: A molecular dynamics simulation study

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Insulin resistance, a key feature of diabetes mellitus, stems from impaired insulin signaling.
• Vitamins D and E are hypothesized to influence diabetes through various mechanisms, including improved glucose metabolism and insulin sensitivity.
• Clinical trial results on vitamin D supplementation for glucose control remain inconsistent.

Purpose of the Study:

• To investigate the molecular interactions of vitamin D3 and E with insulin using computational methods.
• To elucidate the conformational changes in insulin induced by vitamin D3 and E binding.
• To propose a mechanism for insulin activation by vitamin E for potential therapeutic applications.

Main Methods:

• Molecular docking using AutoDock Vina to determine binding modes of vitamins D3 and E to insulin.
• Molecular Dynamics (MD) simulations to analyze conformational changes and stability.
• Binding energy calculations using the Molecular Mechanics-Poisson Boltzman Surface Area (MM-PBSA) method.

Main Results:

• Both vitamins D3 and E demonstrated affinity for insulin, with vitamin E exhibiting higher binding energy (-46 kJ/mol).
• Vitamin E binding induced significant conformational changes in insulin's B-chain, shifting it to a "wide-open/active" form by increasing the ValB12-TyrB26 distance and altering the hinge angle.
• Vitamin D3 binding did not induce comparable conformational changes in the insulin B-chain.

Conclusions:

• Molecular dynamics simulations suggest that vitamin E can activate insulin by promoting a conformational change essential for receptor binding.
• Vitamin E's ability to expose key hydrophobic residues may enhance insulin's interaction with its receptor.
• These findings propose a novel therapeutic model involving vitamin E for modulating insulin signaling in diabetes treatment.