Mechanism of Ligand Recognition by Human ACE2 Receptor

Angiotensin converting enzyme 2 (ACE2) plays a key role in renin–angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV SARS-CoV-2. is also widely expressed epithelial cells of lungs, heart, kidney, pancreas. It considered an important drug target treating SARS-CoV-2 well pulmonary diseases, heart failure, hypertension, renal diabetes. Despite critical importance, mechanism ligand binding to human remains unknown. Here, we have addressed this challenge through all-atom simulations using novel Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond time scale LiGaMD unprecedentedly captured multiple times spontaneous unbinding potent inhibitor MLN-4760 receptor. With far away unbound state, samples distinct Open, Partially Closed, Fully Closed conformations. Upon active site, conformational ensemble biased toward state observed X-ray experimental structure. The thus suggest selection recognition by highly flexible receptor, which expected facilitate rational design targeting against other related diseases.