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bioRxiv · 10.64898/2026.10.27.762289

Laminin-Derived Peptides Bind Neuropilin-1 at the VEGF-A165 Binding Pocket

Veltri, E.·Lovas, S.
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Abstract

Neuropilin-1 (NRP-1) is associated with glioblastoma progression and contains a b1-domain pocket that binds the C-terminal region of VEGF-A165. Whether laminin-derived peptide fragments can associate with this site is unknown. AlphaFold 3 complex prediction followed by 15 s of all-atom production molecular dynamics simulation, trajectory-based pocket occupancy and interaction analyses, and FoldX energetic scoring was performed to compare binding of the laminin-derived pentapeptide Ac-Tyr-Ile-Gly-Ser-Arg-NH2 (peptide 1) with its retro (Ac-Arg-Ser-Gly-Ile-Tyr-NH2, peptide 2) and retro-inverso (Ac-arg-ser-Gly-ile-tyr-NH2, peptide 3) analogs. Peptide 1 showed the highest mean equilibrated occupancy of the canonical VEGF-A165 pocket (60.3 +/- 34.6%) compared with peptide 2 (25.9 +/- 32.7%) and peptide 3 (21.4 +/- 29.5%), while sampling interactions with canonical pocket residues including Asp320, Tyr297, and Tyr353; FoldX binding-energy estimates were similar across peptides despite their differing pocket persistence. Complementary nanoDSF measurements using recombinant NRP-1 and synthetic peptides yielded apparent dissociation constants in the low micromolar range for all three peptides (12.7 M - 33.3 M), providing experimental support for the predicted interactions. These results support persistent, sequence-dependent association of peptide 1 with the VEGF-A165 binding site of b1-NRP-1 and identify peptide analogs as a candidate for further optimization as an NRP-1-binding peptide.

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Veltri, E., Lovas, S.. 2026-10-30. Laminin-Derived Peptides Bind Neuropilin-1 at the VEGF-A165 Binding Pocket. https://doi.org/10.64898/2026.10.27.762289

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