Layer-Wise Relevance Analysis for Motif Recognition in the Activation Pathway of the beta 2-Adrenergic GPCR Receptor

G-protein-coupled receptors (GPCRs) are cell membrane proteins of relevance as therapeutic targets, and are associated to the development of treatments for illnesses such as diabetes, Alzheimer's, or even cancer. Therefore, comprehending the underlying mechanisms of the receptor functional properties is of particular interest in pharmacoproteomics and in disease therapy at large. Their interaction with ligands elicits multiple molecular rearrangements all along their structure, inducing activation pathways that distinctly influence the cell response. In this work, we studied GPCR signaling pathways from molecular dynamics simulations as they provide rich information about the dynamic nature of the receptors. We focused on studying the molecular properties of the receptors using deep-learning-based methods. In particular, we designed and trained a one-dimensional convolution neural network and illustrated its use in a classification of conformational states: active, intermediate, or inactive, of the beta 2-adrenergic receptor when bound to the full agonist BI-167107. Through a novel explainability-oriented investigation of the prediction results, we were able to identify and assess the contribution of individual motifs (residues) influencing a particular activation pathway. Consequently, we contribute a methodology that assists in the elucidation of the underlying mechanisms of receptor activation-deactivation.