Conformational Features, Electronic Structure, and Molecular Docking Studies of H-Trp-Arg-OH and H-Trp-Glu-OH Dipeptides

In this study, the conformational behavior of two dietary dipeptides, H-Trp-Arg-OH (WR) and H‑Trp-Glu-OH (WE), which are agonists of peroxisome proliferator-activated receptor alpha (PPAR-α), was examined using molecular mechanics and molecular dynamics methods. Subsequently, the most stable conformer of each dipeptide, WR and WE, was docked into the PPAR-α ligand-binding domain (PDB ID: 6KB0), DNA (PDB ID: 1BNA), and Human Serum Albumin (HSA; PDB ID: 1AO6) to explore their interaction mechanisms, metabolic roles, and biological activities. The conformational behavior of these dipeptides and the dynamics of their side chains were studied with molecular mechanics, which identified a set of energetically favored conformers. Molecular dynamics studies on the conformational stability of the dipeptides revealed a limited number of stable conformers that tend to adopt unfolded structures. The molecular electrostatic potential (MEP) surface and dipole moment values of the most stable zwitterionic conformation of both dipeptides were calculated at the DFT/B3LYP/6-31++G(d,p) level of theory. Docking studies of WR and WE with DNA (1BNA) showed binding energies of –8.27 and –7.60 kcal/mol, respectively; docking with HSA revealed binding energies of –7.37 and –8.10 kcal/mol, respectively; and docking with 6KB0 showed binding energies of –5.98 and –6.20 kcal/mol, respectively. These docking results clarified the interaction mechanisms between each dipeptide and receptor. Furthermore, the top-scoring WR-6KB0 complex from the docking studies was subjected to 100 ns of all-atom molecular dynamics (MD) simulations to examine the stability of the complex and ligand-receptor interactions in greater detail.