Induction and stabilization of peptide alpha‐helices on silica nanoparticles

Abstract

Stabilizing secondary structure elements is critical to controlling peptide and protein bioactivity, stability, and function. The α‐helix, central to molecular recognition and structural integrity, is a particularly valuable target for stabilization in biotechnological and nanomaterial applications. However, non‐covalent peptide–nanomaterial interactions often lack robustness and reproducibility. We report a covalent immobilization strategy to induce and stabilize α‐helical conformations on amino‐functionalized silica nanoparticles (SNPs). This approach leverages dynamic covalent peptide–surface coupling to enable thermodynamic selection of α‐helical conformations. Alanine‐rich peptides incorporating periodic lysine residues were designed to enable covalent anchoring while promoting helix formation. Immobilization markedly enhances thermal stability compared to free peptides. Systematic variation of lysine positioning shows that terminal attachment induces helicity, whereas incorporation every second helical turn provides optimal conformational and thermal stability. Crucially, the helical face oriented away from the nanoparticle surface remains accessible for molecular recognition. Streptavidin‐binding peptides immobilized via this method retain their specific binding activity while exhibiting superior thermal robustness. This sequence‐guided approach establishes a robust framework for covalent peptide–nanoparticle conjugation, enabling precise secondary structure stabilization and functional biointerfaces for thermally stable protein–protein interaction platforms.