Molecular Dynamics Simulations of Fibril Formation of Chiral Peptides

Two-dimensional infrared (2D IR) spectroscopy experiments have shown that peptide chirality strongly influences fibril formation. Specifically, the number of β-sheets differs when only left-handed peptides are present compared to when both left- and right-handed peptides are combined. Understanding how left- and right-handed peptides assemble—whether through self-assembly (homochiral), mixed assembly (heterochiral), or random association—remains an important open question.

To address this, we performed molecular dynamics simulations on five different peptides. For each peptide, two simulations were carried out under identical conditions (350 K, 2 μs): one with ten left-handed peptides and another with a mixture of five left- and five right-handed peptides. From the simulations, we analyzed secondary structure evolution, Cα and residue arrangements, and hydrogen bond formation within and between homochiral and heterochiral peptide pairs. Additionally, we calculated van der Waals and Coulomb energy changes to evaluate energetic preferences. Together, these results provide molecular-level insight into the role of chirality in peptide fibril formation.