Investigation on the characteristics and mechanisms of ACE inhibitory peptides by a thorough analysis of all 8000 tripeptides via binding free energy calculation

Abstract

Food‐derived angiotensin I‐converting enzyme (ACE) inhibitory peptides represent a potential source of new antihypertensive. However, their characteristics and binding mechanisms were not well understood. In this study, novel energy calculation and experimentation were combined to elucidate the characteristics and mechanisms of ACE inhibitory tripeptides. ACE inhibitory activity of all 8,000 tripeptides was investigated by in silico experiments. IC50 values of the five top‐rated tripeptides ranged from 5.86 to 21.84 μM. Five hundred top‐ranked tripeptides were chosen for detailed structure–activity analysis, and a significant preference for aromatic amino acids at both C‐ and N‐terminus was found. By binding free energy analysis of nine representative tripeptides via MM/GBSA, electrostatic energy was found to be the leading energy that contributed to the binding of ACE with its high affinity tripeptides. Besides, S355, V380, and V518, three residues positioned around the classical binding pockets of ACE, also played a key role in ACE's binding. Therefore, for tripeptides, their binding pockets in ACE were redefined. In conclusion, the characteristics of ACE inhibitory peptides were more deeply illustrated by the thorough analysis of all tripeptides. The energy analysis allows a better understanding of the binding mechanisms of ACE inhibitory peptides, which could be used to redesign the ACE inhibitors for stronger inhibitory activity.

Angiotensin-Converting Enzyme 2 Activation Is Not a Common Feature of Angiotensin-Converting Enzyme Inhibitory Peptides

“…About 200 ACEi tripeptides were selected from the established database as tripeptides usually possess the highest ACEi activity. , Considering the possible discrepancies in the results obtained by different researchers via various methods, selected ACEi peptides were all subjected to molecular docking to predict their interactions with ACE. ACEi activity is usually positively correlated with the binding affinity between ACE and ACEi peptides, , based on which potent ACEi peptides were determined using the binding score.…”

Two novel angiotensin‐converting enzyme (ACE) and dipeptidyl peptidase IV (DPP‐IV) inhibiting peptides from tilapia (Oreochromis mossambicus) skin and their molecular docking mechanism

“…Intermolecular interactions play a crucial role in peptide‐protein binding. DPP‐IV inhibitors interacted with hydrophobic residues in the S1 pocket (Tyr631, Trp659, Tyr662, Tyr666, Val711, and Val656) and the catalytic triad (Ser630, His740, Asp708, and Asn710), as well as charged residues in the S2 pocket (Arg358, Phe357, Ser209, Glu206, Glu205, and Arg125) (Chen et al., 2021). In Figure 7E, GPLGAL was shown to form hydrophobic interactions with key components in the S1 pocket (Tyr662, His740, Tyr666, and Ser630).…”

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

“…By evaluating the inhibitory effect of 8000 tripeptides, our group, Chen et al [ 25 ], showed that potential ACE inhibitory peptides prefer aromatic amino acids at both ends of the peptide, especially at the C-terminus, where Trp-containing tripeptides may have better ACE inhibitory effects. This result is in general agreement with the findings of Panyayai et al [ 26 ] for tripeptides.…”