Abstract
This work describes a computer study that looks at how different amounts of cholesterol (0%, 25%, and 50%) in cell membranes change the relationship between ATP and the K(ATP) channel. This could explain why pancreatic beta-cells secrete insulin differently. We use computer simulations of molecular dynamics, calculations of binding free energy, and an integrated oscillator model to look at the electrical activity of beta-cells. There is a need for this kind of multiscale approach right now because cholesterol plays a part in metabolic syndrome and early type 2 diabetes. Our results showed that the increase in cholesterol concentration in the cell membrane affects the electrostatic interactions between ATP and the K(ATP) channel, especially with charged residues in the binding site. Cholesterol can influence the properties of a membrane, including its local charge distribution near the channel. This affects the electrostatic environment around the ATP-binding site, increasing the affinity of ATP for the channel as our results indicated from 0 to 25 and 50% cholesterol (- 141 to - 113 kJ/mol, respectively). Simulating this change in the affinity to ATP of the K(ATP) channels in a model of the electrical activity of the pancreatic beta-cell indicates that even a minimal increase could produce hyperinsulism. The study answers an important research question about how the structure of the membrane affects the function of K(ATP) and, in turn, insulin releases a common feature of metabolic syndrome and early stages of type 2 diabetes.