G-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and serve as primary targets of ~1/3 of currently marketed drugs. GPCRs are able to transduce extracellular signals across the cell membrane. Upon agonist binding, GPCRs undergo large-scale conformational changes in the transmembrane domain in order to couple with the intracellular proteins for downstream signaling. While much attention has been focused on GPCR activation, it remains unclear how the receptor-membrane interactions depend on different conformational states of the GPCR (e.g., inactive and active), and vice versa. Here, we have explored GPCR-membrane interactions using the adenosine A1receptor (A1AR) as a model system. The A1AR is one of the four subtypes of adenosine receptors and an important therapeutic target for treating human diseases, including cardiac ischemia and neuropathic pain. We have performed all-atom enhanced simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method on both the inactive antagonist-bound and active agonist-Gi protein-bound A1AR. The GaMD simulations have revealed important insights into the protein-membrane interactions during GPCR activation.

Activation dependent G-protein-coupled receptor-membrane interactions

2019 Spring National Meeting

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