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