Computational exploration of naturally derived peptides inhibitory mechanisms against ACE enzyme, from interactions to structural-dynamics

Abstract

Naturally derived peptides have gained significant attention because of their potential to reduce blood pressure. These peptides can be derived from various sources, including snake venom, marine organisms, cow’s milk, seahorses, and plants. Investigating the underlying mechanisms of these peptides in lowering blood pressure is crucial for replacing synthetic drugs currently in use. In this regard, we conducted in silico studies, such as molecular docking, classical molecular dynamics (MD) simulations, and QM/MM simulation methods, on two naturally derived peptides (PAGPRGPA and WALKGYK) and Angiotensin II (ANGII) as the enzyme substrates for binding to sACE. The results of 500 ns MD calculations showed that the WALKGYK peptide occupies the ACE binding site, similar to the ANGII and BPPb peptides, two distinguished C-domain-specific inhibitors. Furthermore, QM/MM calculations demonstrated that no peptide bond cleavage was mediated by Zn2+ at the catalytic site of the peptides. However, during the 500 ns MD simulation, the backbone oxygens of LYS4 and GLY5 of the WALKGYK peptides were tightly coordinated to the Zn2+ ion. Free energy calculations also confirmed the higher affinity of the WALKGYK peptides for binding to sACE. In addition, structural analysis correlation showed a different pattern in PAGPRGPA compared to WALKGYK and ANGII. Despite the similarity of the peptide PAGPRGPA to typical ACE peptide inhibitors with hydrophobic ends, the electrostatic composition of the WALKGYK peptide showed a higher tendency towards ACE inhibition. Therefore, peptide residue compositions, such as WALKGYK, can be considered for designing new inhibitors with fewer side effects for sACE C-terminal inhibitors.