Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.

ABSTRACT: G-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and represent primary targets of ~1/3 of currently marketed drugs. Allosteric modulators have emerged as more selective drug candidates compared with orthosteric agonists and antagonists. However, many X-ray and cryo-EM structures of GPCRs resolved so far exhibit negligible differences upon binding of positive and negative allosteric modulators (PAMs and NAMs). Mechanism of dynamic allosteric modulation in GPCRs remains unclear. In this work, we have systematically mapped dynamic changes in free energy landscapes of GPCRs upon binding of allosteric modulators using the Gaussian accelerated molecular dynamics (GaMD), Deep Learning (DL) and free energy prOfiling Workflow (GLOW). A total of 18 available

SUBMITTER: Do HN 

PROVIDER: S-EPMC9882226 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature