Stability issues of covalently and noncovalently bonded peptide subunits

The present study focuses on important questions associated with modeling of peptide and protein stability. Computing at different levels of theory (RHF, B3LYP) for a representative ensemble of conformers of di‐ and tripeptides of alanine, we found that the Gibbs Free Energy values correlate significantly with the total electronic energy of the molecules (0.922 ≤ R 2 ). For noncovalently attached but interacting peptide subunits, such as [For‐NH 2 ] 2 or [For‐ L ‐Ala‐NH 2 ] 2 , we have found, as expected, that the basis set superimposition error (BSSE) is large in magnitude for small basis set but significantly smaller when larger basis sets [e.g., B3LYP/6‐311++G(d,p)] are used. Stability of the two hydrogen bonds of antiparallel β‐pleated sheets were quantitatively determined as a function of the molecular structure, S10 and S14, computed as 4.0 ± 0.5 and 8.1 ± 1.1 kcal/mol, respectively. Finally, a suitable thermoneutral isodesmic reaction was introduced to scale both covalently and noncovalently attached peptide units onto a common stability scale. We found that a suitable isodesmic reaction can result in the total electronic energy as well as the Gibbs free energy of a molecule, from its “noninteracting” fragments, as accurate as a few tenths of a kcal per mol. The latter observation seems to hold for peptides regardless of their length (1 ≤ n ≤ 8) or the level of theory applied. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1084–1100, 2004