Abstract
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 H14–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 H14–structure of the cationic Ac-dAba-NHMe adopted a left-handed 314-helix, which has a slightly narrower radius and a longer rise than the regular 314-helix of β-peptides. Hence, the 314-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.
Highlights
For two decades, the density functional theory (DFT) has been an efficient computational tool in conformational study of amino acids and peptides [1, 2, 3, 4, 5, 6]
It has been known that typical DFT correlation functionals are designed for the description of short-range correlations, whereas MP2 is superior to DFTs in the description of long-range correlations
No assessment of DFTs has been made for relative conformational energies of charged amino acids or peptides in water, there was an assessment of DFTs for the clusters of the zwitterionic arginine with halide ion (ClÀ and BrÀ) against the benchmark MP2 energies in the gas phase [20]
Summary
The density functional theory (DFT) has been an efficient computational tool in conformational study of amino acids and peptides [1, 2, 3, 4, 5, 6]. It has been known that typical DFT correlation functionals are designed for the description of short-range correlations, whereas MP2 is superior to DFTs in the description of long-range correlations To handle both types of correlations more appropriately, several double-hybrid DFT methods have been proposed, based on a combination of density functionals for exchange and correlation with Hartree-Fock (HF) exchange and a perturbative second-order correlation obtained from Kohn-Sham orbitals [16, 17, 18]. The addition of dispersion corrections has shown improved performance of DFTs when predicting the relative conformational energies of neutral amino acids and peptides against the benchmark CCSD(T)/CBS-limit energies [9, 10, 12, 13, 14, 15, 19]. No assessment of DFTs has been made for relative conformational energies of charged amino acids or peptides in water, there was an assessment of DFTs for the clusters of the zwitterionic arginine with halide ion (ClÀ and BrÀ) against the benchmark MP2 energies in the gas phase [20]
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