Abstract
The inhibition of human angiotensin I converting enzyme (ACE) has been regarded as a promising approach for the treatment of hypertension. Despite research attempts over many years, our understanding the mechanisms of activation and inhibition of ACE is still far from complete. Here, we present results of all atom molecular dynamics simulations of ACE with and without ligands. Two types of inhibitors, competitive and mixed non-competitive, were used to model the ligand bound forms. In the absence of a ligand the simulation showed spontaneous large hinge-bending motions of multiple conversions between the closed and open states of ACE, while the ligand bound forms were stable in the closed state. Our simulation results imply that the equilibrium between pre-existing backbone conformations shifts in the presence of a ligand. The hinge-bending motion of ACE is considered as an essential to the enzyme function. A mechanistic model of activation and the inhibition may provide valuable information for novel inhibitors of ACE.
Highlights
Hypertension, a long-term medical condition known as high blood pressure, is a major risk factor for vision loss, stroke, heart failure and chronic kidney disease, and more than a quarter of the world’s adult population in 2000 had hypertension [1]
In the renin-angiotensin-aldosterone system (RAAS), renin stimulates the generation of angiotensin I (AngI), which is converted to vasoconstrictor angiotensin II (AngII) by angiotensin I converting enzyme (ACE)
We investigated the interactions and dynamics of ACE bound with the mixed non-competitive inhibitor inhibitor further
Summary
Hypertension, a long-term medical condition known as high blood pressure, is a major risk factor for vision loss, stroke, heart failure and chronic kidney disease, and more than a quarter of the world’s adult population in 2000 had hypertension [1]. Therapeutic approaches have focused on the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and electrolyte balance in humans [2]. In the RAAS, renin stimulates the generation of angiotensin I (AngI), which is converted to vasoconstrictor angiotensin II (AngII) by angiotensin I converting enzyme (ACE). Two isoforms (somatic and testicular) of ACE are transcribed by ACE gene in a tissue-specific manner. The somatic form (sACE) is a zinc dependent dicarboxypeptidase, which includes two homologous domains (N domain and C domain) with ~60% sequence identity and the same zinc motif HEXXH (X = any amino acid residue) [3,4]. It has been reported that the C domain of human sACE has the main AngI converting site in controlling blood pressure and cardiovascular functions [5]
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