Dynamic Allosteric Modulation of G-Protein-Coupled Receptors

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 ligands. However, many X-ray and cryo-EM structures of GPCRs resolved so far exhibit negligible differences upon binding of allosteric modulators. Mechanism of dynamic allosteric modulation of GPCRs remains unclear. In this talk, I will present our recent studies in allosteric modulation of adenosine and muscarinic GPCRs by combining cutting-edge cryo-electron microscopy, Gaussian accelerated molecular dynamics (GaMD) simulations and pharmacology experiments^1,2. In addition, we have applied the GaMD, Deep Learning and free energy prOfiling Workflow (GLOW) to map dynamic changes in free energy landscapes of GPCRs upon binding of allosteric modulators. Available high-resolution experimental structures of allosteric modulator-bound class A and B GPCRs were collected and a number of additional computational models were generated by changing target receptors of the modulators to different subtypes. All-atom GaMD simulations were performed for a total of 66 µs on 44 GPCR systems in the presence/absence the modulator. Comprehensive Deep Learning and free energy calculations of the GaMD simulations have provided important mechanistic insights into dynamic allostery of GPCRs and modulator selectivity, which shall greatly facilitate rational design of selective GPCR allosteric drugs.