Interfacial water at the trialanine hydrophilic surface: a DFT electronic structure and bottom-up investigation

Abstract

DFT-M062X quantum chemical computations on the Ala3H(+)·nH2O (n up to 37) complexes have been performed to model for hydration effects on the molecular properties of protonated trialanine. Following simple rules to arrange water molecules around the peptide, geometry optimization allows us to find four minima corresponding to the unfolded extended (β) and polyproline II (PPII) conformations. The peptide is incorporated into the network of hydrogen bonds of interfacial water molecules with a hydration energy of about -85 kcal mol(-1). The progressive hydration of the peptide shows a more efficient intermolecular hydrogen bonding in the PPII arrangement, and the following relative electronic energy stability β-β < β-PPII ≈ PPII-β < PPII-PPII has been found. The conformational entropy term proceeds in the reverse direction, thus these changes compensate in a way that leads to small changes in Gibbs free energy. These findings agree with experimental data which report an equilibrium between these conformers modulated by temperature.

Quantum Mechanics Approach to Hydration Energies and Structures of Alanine and Dialanine

“…For the M06‐2X calculations, the grid mesh in integral evaluation was set to the “Integral(UltraFineGrid)” option, because vibrational frequencies and related zero‐point energy and absolute entropy are sensitive to integral accuracy …”

“…The complete H‐bonded water network surrounding alanine and dialanine (Ala ⋅ 13 H 2 O, Ala 2 ⋅ 18 H 2 O, and Ala 2 H + ⋅ 18 H 2 O) was constructed adding water molecules in a heuristic way . The models were developed by considering that a water molecule can form two H‐bonds as acceptor and two as donor in the optimal coordination geometry, the NH group is an H‐bond donor, and the CO group forms two H‐bonds as acceptor.…”

“…Correct evaluation of H‐bond strength is hard to achieve, even at the quantum chemical level, and often very intensive computational methods are necessary . For instance, the enthalpy variations for the β→PPII transformation of hydrated cationic trialanine, which are well known from experiments, are underestimated when the B3PW91 and TPSS functionals are adopted, whereas they are overestimated (approximately twofold) with the M06‐2X functional . These results emphasize the crucial importance of the electronic‐structure method in the evaluation of peptide–water interactions, and a deeper analysis with more reliable computational methods that treat electronic correlation in unbiased way, such as MP2, MP4‐SDQ, and CCSD(T), is desirable …”

“…Considering that amino acid (peptide)–water complexes play a crucial role in the process of connecting molecular properties to those of the bulk, a computational procedure based on true ab initio electronic‐structure methods together with a “chemical‐logic” bottom‐up approach has been proposed to inquire into hydration phenomena . In this approach short‐range solute–solvent interactions are considered in terms of discrete numbers of water molecules sufficient to wrap the peptide and optimize the synergy in the H‐bond network.…”

“…Despite appreciable results, some criticalities related to the enthalpy and entropy variations among various conformers with extended (β) and polyproline type II (PPII) arrangements were evident . Correct evaluation of H‐bond strength is hard to achieve, even at the quantum chemical level, and often very intensive computational methods are necessary .…”