Ultraslow water-mediated transmembrane interactions regulate the activation of A$_{\text{2A}}$ adenosine receptor

TL;DR

This study uses microsecond molecular dynamics simulations to reveal that ultraslow water molecules within the transmembrane domain of the A2A adenosine receptor play a crucial role in its activation by forming a unique allosteric network.

Contribution

It uncovers the dynamics and functional significance of internal water molecules in GPCR activation, highlighting ultraslow water relaxation as a key factor.

Findings

Water flux varies with receptor state, slower in active form.

Water residence times range from hundreds of picoseconds to hundreds of nanoseconds.

Ultraslow waters form a continuous allosteric network in the active state.

Abstract

Water molecules inside G-protein coupled receptor have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal waters in GPCR activity, we studied A$_{\text{2A}}$ adenosine receptor using $\mu$sec-molecular dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times slower than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from $\sim\mathcal{O}(10^2)$ psec to $\sim\mathcal{O}(10^2)$ nsec. Especially, water molecules, exhibiting ultraslow relaxation ($\sim\mathcal{O}(10^2)$ nsec) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow waters in the GPCR activation.