# Mechanistic insights into dimerization and cross-β sheet formation in the HIV-associated amyloidogenic peptide PAP248–286 from unbiased all-atom molecular dynamics simulations

## TL;DR

This study uses molecular simulations to uncover how the HIV-related peptide PAP248–286 forms structures that help spread the virus.

## Contribution

The study provides atomistic insights into the early dimerization and β-sheet formation mechanisms of PAP248–286 using extensive unbiased simulations.

## Key findings

- Peptide association and β-sheet formation are driven by hydrogen bonding and hydrophobic interactions.
- Residues Arg10, Val17, Glu19, and Ile20 are key to inter-peptide binding.
- Dissociation free energy is ∼8.7 kcal/mol, showing a clear thermodynamic separation between bound and unbound states.

## Abstract

Semen-derived enhancer of viral infection (SEVI) fibrils, assembled from the peptide fragment PAP248–286, enhance HIV transmission by promoting viral attachment to host cells. However, the molecular basis of SEVI nucleation and early aggregation remains unclear. Here, we conducted 80 independent all-atom molecular dynamics (MD) simulations spanning a total of 40 μs, together with 100 independent steered MD and umbrella sampling runs, to explore the dimerization and dissociation of PAP248–286. Our results indicate that peptide association and β-sheet formation are governed by a cooperative interplay between hydrogen bonding and hydrophobic interactions. Residue-level analyses identified Arg10, Val17, Glu19, and Ile20 as key contributors to inter-peptide binding, consistent with steric zipper motifs described in other amyloid systems. Steered MD revealed mechanically resilient dimers with average rupture forces of ∼20 kcal/mol/Å and multi-barrier unbinding behavior. Umbrella sampling estimated a peptide dissociation free energy of ∼8.7 kcal/mol, highlighting a clear thermodynamic separation between bound and unbound states. Together, these findings suggest that small β-sheet nuclei in PAP248–286 dimers act as cooperative intermediates that seed the formation of full-length cross-β structures, providing atomistic insights into the earliest steps of SEVI fibril assembly.