The full activation mechanism of the adenosine A 1 receptor revealed by GaMD and Su-GaMD simulations

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-10, Vol.119 (42), p.e2203702119
• Main Authors: Li, Yang, Sun, Jixue, Li, Dongmei, Lin, Jianping
• Format: Article
• Language: English
• Subjects: Adenosine; GTP-Binding Proteins - metabolism; Ligands; Molecular Dynamics Simulation; Receptor, Adenosine A1 - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Purinergic P1 - metabolism; Thermodynamics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2203702119

The full activation process of G protein-coupled receptor (GPCR) plays an important role in cellular signal transduction. However, it remains challenging to simulate the whole process in which the GPCR is recognized and activated by a ligand and then couples to the G protein on a reasonable simulation timescale. Here, we developed a molecular dynamics (MD) approach named supervised (Su) Gaussian accelerated MD (GaMD) by incorporating a tabu-like supervision algorithm into a standard GaMD simulation. By using this Su-GaMD method, from the active and inactive structure of adenosine A receptor (A R), we successfully revealed the full activation mechanism of A R, including adenosine (Ado)-A R recognition, preactivation of A R, and A R-G protein recognition, in hundreds of nanoseconds of simulations. The binding of Ado to the extracellular side of A R initiates conformational changes and the preactivation of A R. In turn, the binding of G to the intracellular side of A R causes a decrease in the volume of the extracellular orthosteric site and stabilizes the binding of Ado to A R. Su-GaMD could be a useful tool to reconstruct or even predict ligand-protein and protein-protein recognition pathways on a short timescale. The intermediate states revealed in this study could provide more detailed complementary structural characterizations to facilitate the drug design of A R in the future.