Interpreting the structural mechanism of action for MT7 and human muscarinic acetylcholine receptor 1 complex by modeling protein-protein interaction

MT7 is a selective human muscarinic acetylcholine receptor 1 (hM1) allosteric binder with subnanomolar affinity. Understanding the binding mode of hM1-MT7 will give insights to discover small molecular ligand for hM1. MT7 is a peptide, and hM1 is a G-protein-coupled membrane receptor. Therefore, we have employed homology modeling, protein-protein docking, explicit membrane molecular dynamics (MD) simulations, and molecular mechanic/Poisson-Boltzmann surface area energy decomposition analysis approaches to reveal the hM1-MT7 binding mode. The binding mode is consistent with the experimental data. We have discovered that the binding mode consists of three interaction regions in five residue interaction clusters. By analyzing the cluster representative structures, the cluster residues form an interaction network, which shows a multiple-point-to-site binding mode. Hydrogen binding statistical analysis reveals that E170 (hM1) and R34 (MT7) are both locked in electrostatic cages with counter charges, respectively. This is confirmed by the dynamic distances calculation between these residues, and biological mutant experiments.