Abstract

--- - Proper description of solvent effects is challenging for theoretical methods, particularly if the solute is a zwitterion. Here, a series of theoretical procedures are used to determine the preferred solvated conformations of twelve hydrophobic dipeptides (Leu-Leu, Leu-Phe, Phe-Leu, Ile-Leu, Phe-Phe, Ala-Val, Val-Ala, Ala-Ile, Ile-Ala, Ile-Val, Val-Ile and Val-Val) in the zwitterionic state. First, the accuracy of density functional theory (DFT), combined with different implicit solvent models, for describing zwitterions in aqueous solvent is assessed by comparing the predicted against the experimental glycine tautomerization energy, i.e., the energetic difference between canonical and zwitterionic glycine in aqueous solvents. It is found that among the tested solvation schemes, the charge-asymmetric nonlocally determined local-electric solvation model (CANDLE) predicts an energetic difference in excellent agreement with the experimental value. Next, DFT-CANDLE is used to determine the most favorable solvated conformation for each of the investigated dipeptide zwitterions. The CANDLE-solvated structures are obtained by exploring the conformational space of each dipeptide zwitterion concatenating DFT calculations, in vacuum, with classical molecular dynamics simulations, in explicit solvents, and DFT calculations including explicit water molecules. It is found that the energetically most favorable conformations are similar to those of the dipeptide zwitterions in their respective crystal structures. Such structural agreement is indicative of the DFT-CANDLE accomplishment of the description of solvated zwitterions, and suggests that these biomolecules self-assemble as quasi-rigid objects. - It is shown that the charge-asymmetric nonlocally determined local-electric solvation model (CANDLE) together with density functional theory adequately describes peptide zwitterions in aqueous solvents.