QM/MM Study and MD Simulations on the Hypertension Regulator Angiotensin-Converting Enzyme

Abstract

Human angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that converts angiotensin I to the vasoconstrictor angiotensin II and inactivates the vasodilator bradykinin. This dual ability is vital to blood pressure regulation and management of hypertension. Despite the many enzymatic studies on zinc metallopeptidases, the correct substrate binding mode and catalysis of ACE are still not completely understood. Two buried chloride ions activate the ACE hydrolysis efficiency in a substrate-dependent manner, but the molecular mechanism associated with this activation also remains unclear. In this work, the catalytic mechanism of ACE was studied with atomistic detail, using a hybrid quantum mechanical/molecular mechanical method at the ONIOM(M06-2X/6-311+G(d,p):Amber//B3LYP/6-31G(d):Amber) level. The hydrolytic reaction proceeds via a general acid/base mechanism, in which the first mechanistic step involves the displacement of the zinc-bound water molecule that performs a nucleophilic attack on the sc...