Machine Annealing-guided Navigation of Antihypertensive Food Peptide Selectivity between Human ACE N- and C-domains in Structurally Interacting Diversity Space.

Human angiotensin-converting enzyme (ACE) is a well-established druggable target for treatment of hypertension (HTN), which contains two structurally homologous but functionally distinct N- and C-domains. Selective inhibition of the C-domain primarily contributes to the antihypertensive efficiency and can be exploited as medicinal agents and functional additives for regulating blood pressure with high safety. In this study, we used a machine annealing (MA) strategy to guide the navigation of antihypertensive peptides (AHPs) in structurally interacting diversity space with the two ACE domains based on their crystal/modeled complex structures and an in-house protein-peptide affinity scoring function, aiming to optimize the peptide selectivity for C-domain over N-domain. The strategy generated a panel of theoretically designed AHP hits with a satisfactory C-over-N (C>N) selectivity profile, from which several hits were found to have a good C>N selectivity, which are roughly comparable with or even better than the BPPb, a natural C>N-selective ACE-inhibitory peptide. Structural analysis and comparison of domain-peptide noncovalent interaction patterns revealed that (i) longer peptides (> 4 amino aids) generally exhibit stronger selectivity than shorter peptides (< 4 amino aids), (ii) peptide sequence can be divided into two section I (including peptide C-terminal region) and section II (including peptide middle and N-terminal regions); the former contributes to both peptide affinity (primarily) and selectivity (secondarily), while the latter is almost only responsible for peptide selectivity, and (iii) charged/polar amino acids confer to peptide selectivity relative to hydrophobic/nonpolar amino acids (that confer to peptide affinity). This article is protected by copyright. All rights reserved.