Study on the structure–activity relationship of watermelon seed antioxidant peptides by using molecular simulations

Our previous studies had shown that watermelon seed antioxidant peptides (WSAPs: P1-P5) possessed good activities. However, the structure–activity relationship of P1 is still unclear. Quantum chemistry and molecular docking were used to investigate the antioxidant mechanism of P1. The active site of P1 is located at C6H14 on Arg. P1 can bind to DPPH/ABTS through hydrogen bond and hydrophobic interaction. Compared with P2-P4, P1 has the strongest antioxidant capacity. The molecular simulation showed that P1 could enhance the stability of Keap1 by interacting with Asn382, Arg380 and Tyr 334 in the active sites. Compared with the model group, the expression of Keap1 was down-regulated (p < 0.05), while the expression of Nrf2 and HO-1 was up-regulated (p < 0.05) after P1 treatment. P1 has the potential ability to activate the signaling pathway Keap1-Nrf2 and improve the antioxidant defense system. This study provides a new perspective for the rational design and mechanism of antioxidant peptides.