Comparative docking analysis of cholesterol analogs to ion channels to discriminate between stereospecific binding vs. stereospecific response

ABSTRACTCholesterol is a major component of the membrane and a key regulator of many ion channels. Multiple studies showed that cholesterol regulates ion channels in a stereospecific manner, with cholesterol but not its chiral isomers having a functional effect. This stereospecificity has been universally attributed to the specificity of cholesterol binding, with the assumption that only native cholesterol binds to the channels whereas its isomers do not. In this study, we challenge this paradigm by docking analyses of cholesterol and its chiral isomers to five ion channels whose response to cholesterol was shown to be stereospecific, Kir2.2, KirBac1.1, TRPV1, GABAA and BK. The analysis is performed using AutoDock Vina to predict the binding poses and energies of the sterols to the channels and identify amino acids interacting with the sterol molecules. We found that for every ion channel tested herein all three sterols showed similar binding poses and significant overlap in the set of the amino acids tha...