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Angiotensin-converting enzyme (ACE) is a well-known zinc metalloenzyme whose physiological functions are vital to blood pressure regulation and management of hypertension. The development of more efficient peptide inhibitors is of great significance for the prevention and treatment of hypertension. In this research, molecular dynamics (MD) simulations were implemented to study the specific binding mechanism and interaction between human ACE (hACE) and tetrapeptides, YIHP, YKHP, YLVR, and YRHP. The calculation of relative binding free energy on the one hand verified that YLVR, an experimentally identified inhibitor, has a stronger inhibitory effect and, on the other hand, indicated that YRHP is the "best" inhibitor with the strongest binding affinity. Inspection of atomic interactions discriminated the specific binding mode of each tetrapeptide inhibitor with hACE and explained the difference of their affinity. Moreover, in-depth analysis of the MD production trajectories, including clustering, principal component analysis, and dynamic network analysis, determined the dynamic correlation between tetrapeptides and hACE and obtained the communities' distribution of a protein–ligand complex. The present study provides essential insights into the binding mode and interaction mechanism of the hACE–peptide complex, which paves a path for designing effective anti-hypertensive peptides. [ABSTRACT FROM AUTHOR]

This study explored the neuroprotective effect of the peptide LYLKPR derived from fermented yak milk by Lactiplantibacillus plantarum JLAU103 on H 2 O 2 -injured HT-22 cells. Peptide LYLKPR showed good stability in the simulated gastrointestinal tract and strong penetrating ability of the blood-brain barrier (BBB) in vitro . LYLKPR could activate the Nrf2/Keap-1/HO-1 pathway, increase the activities of SOD and CAT, and reduce the levels of ROS and MDA in HT-22 cells. In addition, LYLKPR controlled the activation of the NLRP3 inflammasome by inhibiting the oxidative stress, ultimately preventing the cleavage of pro-IL-18 and pro-IL-1β by caspase-1, and reducing the level of intracellular mature IL-18 by 29.08%. Based on the molecular docking verification, LYLKPR could effectively bind to the Keap-1 protein, and directly inhibit the inflammasome to significantly increase intracellular BDNF, synaptophysin, and PSD95, and protect synaptic function. Collectively, LYLKPR ameliorated oxidative stress-mediated neuronal injury by inhibiting the NLRP3 inflammasome via modulation of the Nrf2/Keap-1/HO-1 pathway.