In silico analysis of PERK interactions with engineered alpha lactalbumin peptides using molecular dynamics simulations

This study integrates docking, molecular dynamics (MD) simulation, and free energy estimation to evaluate two engineered peptides, mutated peptide 52 (MuP52) and mutated peptide 250 (MuP250), derived from α-lactalbumin (α-LA), as potential modulators of protein kinase RNA-like endoplasmic reticulum kinase (PERK). Molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations revealed that MuP250 exhibited slightly stronger overall binding to mouse PERK (mPERK) (ΔG = − 25.84 ± 5.27 kJ/mol) compared to MuP52 (ΔG = − 24.13 ± 6.14 kJ/mol), despite forming fewer hydrogen bonds. Both peptides stabilized the PERK αG-helix region without inducing major structural perturbations, as indicated by analyses of RMSD, RMSF, Rg, SASA, and hydrogen-bonding patterns. In human PERK (hPERK), MuP52 maintained stable binding (ΔG = − 22.79 ± 3.64 kJ/mol) and reduced local flexibility, suggesting potential cross-species relevance. Peptide binding also modulated the conformational landscape under conditions of endoplasmic reticulum (ER) stress, with principal component analysis (PCA) confirming that MuP250 induced the greatest stabilization in mPERK. These results support the structural plausibility of αG-helix engagement by α-LA–derived peptides in the context of Parkinson’s disease (PD) and highlight the roles of hydrogen-bonding and nonpolar interactions in stabilization. The findings are derived exclusively from MD simulations and future in vitro and in vivo validation will be required to confirm the biological relevance and therapeutic potential of these peptides.