Stability issues of covalently and noncovalently bonded peptide subunits

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Abstract

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 ≤ R2). For noncovalently attached but interacting peptide subunits, such as [For-NH2]2 or [For-L-Ala-NH2]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

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