BPS2026 – Predicting hydrophobicity of short peptides via molecular dynamics and alchemical free-energy simulations

Peptides, especially short peptides, are gaining a lot of attention for their interaction with cell membranes. Short amino acid sequences can stick to the surface, slide into lipid layers, or help fold proteins. Because of their built-in flexibility, they're increasingly being explored as alternative agents to antibodies in biological and medical research. This project focuses on how slight changes in peptide sequence affect the way they act in different environments. Specifically, we studied eight pentapeptides—each five amino acids long—with the same beginning and end residues but different sets in the middle. In order to observe how these differences affect hydrophobicity and structural dynamics, we conducted molecular dynamics simulations in two solvents—polar water and nonpolar octanol, which is oily. These simulations allowed us to observe the shape and movement of each peptide change over time in each setting. We also used free-energy perturbation (FEP) calculations to gauge how much energy it would take to shift each peptide from water into octanol. This value, known as transfer free energy, informs us about whether or not a peptide is hydrophobic or hydrophilic—essentially if it prefers water or oil-like conditions. By contrasting peptides with sequences differing by only a few residues, we could identify which residues or motifs make one environment more favored than another. This is essential for the design of new peptides with desired solubility, membrane binding, or therapeutic function. Whether the goal is to create better drug carriers or simply to understand protein behavior, how sequence influences solvent interaction is part of the puzzle.