Molecular basis of angiotensin-converting enzyme 1 selectivity of food-derived anti-hypertensive peptides.

Angiotensin converting enzyme 1 (ACE1) is a key regulator of the renin-angiotensin system. Given that the catalytic domains of the ACE homologs are highly similar, ACE1 inhibitory peptides may inadvertently interfere with ACE2, potentially disrupting RAS homeostasis. Here, we investigated the molecular basis of ACE1/ACE2 selectivity for six naturally occurring food-derived antihypertensive peptides and seven sequence reordered variants. In-vitro ACE1 and ACE2 inhibition assays were combined with molecular docking and 500 ns molecular dynamics (MD) simulations. The natural peptides IPP, IRW, YAKPVA and VPP showed the lowest IC₅₀ values against ACE1, whereas the modified analogues displayed markedly weaker inhibition. Our docking and MD trajectories revealed that the peptides form a network of interactions within the ACE1 active site. However, docking to ACE2 yielded weaker binding and negligible ACE2 inhibition. Overall, our results provide residue-level structural insights that could inform future design of ACE1-selective peptides that spare or potentially activate ACE2.