From Infinite Helices to β Sheets: Structural Insights from Electronic Structure Calculations

Protein folding and aggregation are governed by the balance between helical and sheet conformations, yet their intrinsic energetics remain elusive. Here, we employ periodic density functional theory (DFT) to characterize the conformational landscape of polyalanine in the gas phase and aqueous environments at 0 K. Infinite one- and two-dimensional models capture the full extent of intrastrand and interstrand hydrogen bonding, overcoming the limitations of capped oligomers. Our results show that α-helices are favored in isolated chains, but β sheets gain substantial stability with increasing strand number due to the full hydrogen-bond saturation, ultimately competing with or exceeding helices in the infinite-sheet limit. Solvation reduces energy barriers for helix-to-sheet transitions, facilitating structural rearrangements relevant to folding and misfolding pathways. These findings rationalize why β sheets prevail in supramolecular assemblies, such as amyloids and fibrous proteins, and establish periodic DFT as a powerful tool to probe the intrinsic stability of protein secondary structures in condensed-phase environments.