Conformational preferences of cationic β-peptide in water studied by CCSD(T), MP2, and DFT methods

The conformational preferences of the cationic nylon-3 βNM [(3R,4)-diaminobutanoic acid, dAba] dipeptide in water were explored as the first step to understand the mode of action of polymers of βNM against phylogenetically diverse and intrinsically drug-resistant pathogenic fungi. The CCSD(T), MP2, M06-2X, ωB97X-D, B2PLYP-D3BJ, and DSD-PBEP86-D3BJ levels of theory with various basis sets were assessed for relative energies of the 45 local minima of the cationic Ac-dAba-NHMe located at the SMD M06-2X/6-31+G(d) level of theory in water against the benchmark CCSD(T)/CBS-limit energies in water. The best performance was obtained at the double-hybrid DSD-PBEP86-D3BJ/def2-QZVP level of theory with RMSD = 0.12 kcal/mol in water. The M06-2X/def2-QZVP level of theory predicted reasonably the conformational preference with RMSD = 0.38 kcal/mol in water and may be an alternative level of theory with marginal deviations for the calculation of conformational energies of relatively longer cationic peptides in water. In particular, the H(14)–helical structures appeared to be the most feasible conformations for the cationic Ac-dAba-NHMe populated at 48–64% by relative free energies in water. The hexamer built from the H(14)–structure of the cationic Ac-dAba-NHMe adopted a left-handed 3(14)-helix, which has a slightly narrower radius and a longer rise than the regular 3(14)-helix of β-peptides. Hence, the 3(14)-helices of oligomers or polymers of the cationic dAba residues are expected to be the active conformation to exhibit the ability to bridge between charged lipid head groups that might cause a local depression or invagination of the membrane of fungi.