On the role of nuclear quantum effects on the stability of peptides

Nuclear quantum effects (NQEs) arising from the light mass of hydrogen can influence the structure and stability of hydrogen-bonded biomolecules, yet their role in determining peptide and protein folding remains unclear. Experiments show that substituting H$_2$O with D$_2$O often stabilizes folded states, but the microscopic mechanism associated with this phenomena remains unresolved. Through ab initio-level path-integral molecular dynamics simulations enabled by machine-learning interatomic potentials, we address the fundamental question of the role of NQEs in peptides by investigating both their overall impact and isotope substitution effects. Overall, NQEs systematically destabilize compact three-dimensional structures across peptide systems, independent of secondary structure type or side-chain interactions. Contrary to the conventional picture that places central importance on hydrogen bonds, we find that the dominant destabilization instead arises from the quantum C-H vibrations. In addition, we reveal microscopic insights into the stabilization of folded peptides upon H$_2$O to D$_2$O substitution, showing that the H/D isotope substitution of active peptide hydrogens, previously considered unimportant, produces free-energy changes within the range of experimentally observed shifts. These findings provide a new interpretation of isotope effects in biological systems, indicating that seemingly small H$\to$D substitutions within peptides can be as important as, or even outweigh, solvent contributions.