The development of drugs that act as highly ion channel-specific modulators remains challenging. Unlike soluble proteins, ligands can reach ion channels via hydrophilic pathways (diffuse to the pore from extracellular or intracellular sides) or lipophilic pathways (partition in lipid bilayers first before diffuses to binding sites). While numerous work has been done on the small molecule binding in the aqueous phase, much less attention has been given to ligands that bind to the transmembrane region through the lipophilic pathway. Here we report the first effort in computing a full thermodynamic circle of a small molecule agonist Yoda1 that binds to the transmembrane region of the mechanosensitive channel Piezo1, in a state-dependent manner. We show that hydrophobic molecules that bind to transmembrane regions have higher mobility than traditional protein-ligand interactions anchored by hydrogen bonds. A set of flat-bottom harmonic restraints are designed to capture the high ligand mobility during free energy perturbation while reducing the number of geometric restraints down to two. More importantly, the stronger binding affinity of Yoda1 in Piezo1 open conformation than in closed conformation provided quantitative evidence of the reported Piezo1’s agonist binding site.

Computing binding affinity at transmembrane region: A case study of PIEZO1 channel agonist

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.