Unsupervised Classification of G‑Protein CoupledReceptors and Their Conformational States Using IChem IntramolecularInteraction Patterns

Over the past decade, the ever-growing structural information on G-protein coupled receptors (GPCRs) has revealed the three-dimensional (3D) characteristics of a receptor structure that is competent for G-protein binding. Structural markers are now commonly used to distinguish GPCR functional states, especially when analyzing molecular dynamics simulations. In particular, the position of the sixth helix within the seven transmembrane domains (TMs) is directly related to the coupling of the G-protein. Here, we show that the structural pattern defined by transmembrane intramolecular interactions (hydrogen bonds excluding backbone/backbone interactions, ionic bonds and aromatic interactions) is suitable for comparison of GPCR 3D structures and unsupervised distinction of the receptor states. First, we analyze a microsecond long molecular dynamic simulation of the human s2-adrenergic receptor (ADRB2). Clustering of the 3D structures by pattern similarity identifies stable states which match the conformational...