Structural basis for the anti-aging effects of hydroxyproline-BCAA dipeptides: An integrated computational and...

This study systematically investigated the structure-activity relationships of nine hydroxyproline-branched-chain amino acid dipeptides to elucidate their anti-aging potential. Quantum chemical calculations revealed that electronic properties, particularly a lower HOMO-LUMO energy gap (ΔE) and chemical hardness (η), were critical structural determinants governing the peptides' radical scavenging efficiencies against DPPH^• and ABTS^•+. Structurally flexible linear dipeptides consistently outperformed their rigid cyclic analogues, potently suppressing pro-inflammatory mediators (TNF-α, IL-6) in RAW264.7 macrophages and extending Caenorhabditis elegans lifespan by up to 15 % through enhancing endogenous antioxidant defenses. Molecular docking provided a structural basis for these activities, demonstrating favorable binding affinities to the Keap1-Kelch domain and TNF-α. A composite bioactivity score derived from multivariate analysis identified Hyp-Ile and Leu-Hyp as the most potent candidates. Notably, Hyp-Ile's specific structure conferred the lower energy gap (ΔE = 6.11 eV), which directly translated to markedly higher radical scavenging activity (91.58 % for DPPH^•; 88.58 % for ABTS^•+) compared to its analogues and the stronger binding affinities to Keap1 (-7.111 kcal/mol) and TNF-α (-6.168 kcal/mol), establishing a clear mechanistic link between its electronic configuration and multifaceted bioactivity. These findings position Hyp-Ile and Leu-Hyp as promising, structurally-defined functional food ingredients.