p Calculations of GPCRs: Understanding Protonation States in Receptor Activation.

The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation-conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp residue in five different class A GPCRs (active and inactive conformations) using a linear response approximation (LRA) p calculation protocol. We observed consistent differences (1.3 p units) for the macroscopic p values between the inactive and active states of the A2AR and B2AR receptors, indicating the protonation of Asp during GPCR activation. This process seems to be specific and not conserved, as no differences were observed in the p values of the remaining receptors (CB1R, NT1R, and GHSR).