Temporally Resolved and Interpretable Machine Learning Model of GPCR conformational transition

Identifying target-specific drugs remains a challenge in pharmacology, especially for highly homologous proteins such as dopamine receptors D ₂ R and D ₃ R. Differences in target-specific cryptic druggable sites for such receptors arise from the distinct conformational ensembles underlying their dynamic behavior. While Molecular Dynamics (MD) simulations has emerged as a powerful tool for dissecting protein dynamics, the sheer volume of MD data requires scalable and unbiased data analysis strategies to pinpoint residue communities regulating conformational state ensembles. We have developed the Dynamically Resolved Universal Model for BayEsiAn network Tracking (DRUMBEAT) interpretable machine learning algorithm and validated it by identifying residue communities that enable the deactivation of the β ₂ -adrenergic receptor. Further, upon analyzing dopamine receptor dynamics we identified distinct and non-conserved residue communities around the contacts F170 ^4.62 _F172 ^ECL2 and S146 ^4.38 _G141 ^34.56 that are specific to D ₃ R conformational transitions compared to D ₂ R. This information can be tapped to design subtype-specific drugs for neuropsychiatric and substance use disorders.