Molecular insights into the impact of nanotube confinement on protein α-helical structures

Understanding the stability of α-helical structures under nanotube confinement is essential for elucidating protein folding in vestibules and optimising drug delivery into living cells. However, a systematic investigation is needed to fully understand how varying levels of confinement affect α-helices. In this study, we conducted classical molecular dynamics (MD) simulations with explicit solvents to study four α-helical peptides confined within carbon nanotubes (CNTs) of varying diameters (1.36–2.98 nm). Peptides interact with CNT inner walls through van der Waals interactions, hydrophobic interactions, and π-π stacking. Our results indicate that peptide helicity generally decreases with increasing CNT diameters. Confinement restricts peptide mobility and structural extension, while larger nanotubes provide more space for structural fluctuations, leading to α-helix destabilisation. A transition from ‘slight’ to ‘dramatic’ structural disruption occurs within an approximate diameter range of 1.90–2.17 nm for the investigated CNTs. Additionally, binding free energy analysis reveals that peptides strongly interact with smaller CNTs, where binding occurs along the entire nanotube surface, whereas larger CNTs promote weaker, localised adsorption. Water solvation further weakens peptide-CNT interactions, particularly in the first hydration shell. This study offers insights into the effects of nanotube confinement on α-helical stability, with implications for biomolecular engineering.