Cholesterol Concentration in Cell Membranes and its Impact on Receptor-Ligand Interaction: A Computational Study of ATP-Sensitive Potassium Channels and ATP Binding.

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.