Quantum Mechanics Study on Hydrophilic and Hydrophobic Interactions in the Trivaline-Water System

With the aim to elucidate hydrophobic effects in the unfolded state of peptides, DFT-M062X computations on the Val₃H⁺· nH₂O ( n up to 22) clusters have been accomplished. As far as the main chain is concerned, four conformers with β-strand and/or polyproline type II conformations, PPII (indicated as β-β, β-PPII, PPII-β, and PPII-PPII), have been found by changing the ϕ and ψ angles. For bare peptide, the side chain (isopropyl) of each residue can independently take on three different orientations with negligible effects on energetics. The great isopropyl spatial separations in β-β and β-PPII conformers allow for the construction of synergic and extensive water-water and water-peptide H-bonding in the minimal hydration Val₃H⁺·22H₂O models without significant steric encumbrance. Conversely, due to the proximity of the isopropyl of the central residue with the other two, some restrictions in the water shell construction around the peptide become evident for the PPII-PPII conformer and the number of energetically accessible structures decreases. This is indicative of correlated motion involving isopropyls and backbone mediated by water molecules, the origin of the nearest neighbor effects. Comparing the thermodynamic data of Ala₃H⁺·22H₂O and Val₃H⁺·22H₂O, what emerges is that both hydration enthalpy and entropy drive the β-strand stability of the latter.