Gaussian Accelerated Molecular Dynamics Simulations Investigation on the Mechanism of Angiotensin-Converting Enzyme (ACE) C-Domain Inhibition by Dipeptides

Abstract

Angiotensin-converting enzyme (ACE)-inhibitory peptides extracted from food proteins can lower blood pressure by inhibiting ACE activity. A recent study showed that the inhibitory activity of IY (Ile-Tyr, a dipeptide derived from soybean protein) against ACE was much higher than that of LL (Leu-Leu), although they had similar hydrophobic and predicted activity values. It was difficult to reveal the deep molecular mechanism underlying this phenomenon by traditional experimental methods. The Apo and two complex systems (i.e., ACE–LL and ACE–IY) were therefore subjected to 1 μs long Gaussian accelerated molecular dynamics (GaMD) simulations. The results showed that the binding of IY can cause obvious contraction of the active site of ACE, mainly manifested by a significant lateral shift of α13, α14, and α15. In addition, hinge 2 and hinge 3 were more stable in the ACE–IY system, while these phenomena were not present in the ACE–LL system. Moreover, the α10 of the IY-bound ACE kept an inward state during the simulation progress, which facilitated the ACE to remain closed. However, for the LL-bound ACE, the α10 switched between two outward states. To sum up, our study provides detailed insights into inhibitor-induced conformational changes in ACE that may help in the design of specific inhibitors targeting ACE for the treatment of hypertension.

Antihypertensive Effect, ACE Inhibitory Activity, and Stability of Umami Peptides from Yeast Extract

“…In summary, LLLLPKP was hydrolyzed to small peptide sequences after digestion, but its activity was not impacted that much, owing to the abundant presence of peptide segments with potential ACE inhibitory activity, especially LLLLPK, LLLL, and LPKP. Notably, many other factors affect the peptide–ACE interactions, such as the spatial conformation of the peptide and the conformational changes in ACE upon peptide binding . Furthermore, the properties and activities of the 14 segments are further investigated in our following studies in vitro and in vivo.…”

“…This suggests that LL might lack ACE inhibitory activity, consistent with a previous study. 40 Then, the key binding sites of ACE interacting with 14 peptide segments and LLLLPKP were further analyzed using a clustering heat map (Figure 6). The binding mode of cluster 1 (LLLLPK, LLLL, LLLPK, and LPKP) was similar to that of LLLLPKP, as evident from their interaction with the key sites in pocket S1, S2, and pocket of Zn 2+ .…”

“…Notably, many other factors affect the peptide−ACE interactions, such as the spatial conformation of the peptide and the conformational changes in ACE upon peptide binding. 40 Furthermore, the properties and activities of the 14 segments are further investigated in our following studies in vitro and in vivo. In summary, LLLLPKP was hydrolyzed to smaller peptide sequences after digestion, but its activity was retained due to the abundant presence of peptide segments with potential ACE inhibitory activity, especially LLLLPK, LLLL, and LPKP.…”

Exploration of the Product Specificity of chitosanase CsnMY002 and Mutants Using Molecular Dynamics Simulations

“…Amber 16 software [ 22 , 23 ] was used to simulate the systems consisting of free WT, WT-(GlcN) 2 , G21K-(GlcN) 2 and G21R-(GLCN) 2 for 100 ns. The force field for the protein was Amber FF99SB [ 24 , 25 ], whereas for (GLCN) 2 it was GAFF2 [ 26 , 27 ].…”

Revealing the Sequence Characteristics and Molecular Mechanisms of ACE Inhibitory Peptides by Comprehensive Characterization of 160,000 Tetrapeptides

“…Blood pressure is regulated by a number of metabolic pathways, the most important of which are the renin–angiotensin system (RAS) [ 6 ] and the kallikrein–kinin system (KKS) [ 7 ]. Angiotensin-converting enzyme (ACE) [ 8 ] is one of the key regulators of these two systems, and is an important target for the study of antihypertensive drugs [ 9 , 10 ]. The main treatment for chronic conditions is medication, but unlike acute conditions, the side effects of powerful drugs may be more harmful than the chronic disease itself.…”