Quantum Mechanics Studies of the Intrinsic Conformation of Trehalose

Abstract

To resolve controversies over the intrinsic shape of the disaccharide α,α-trehalose and the magnitude of solvent effects, energy surfaces have been computed at different levels of molecular orbital and density functional theory. All quantum mechanical (QM) levels agree that the gauche linkage conformations observed by experimental crystallographic and solution studies are 5−7 kcal/mol lower in energy than that of the trans shape. This is quite different than the findings of the two most recent classical force field studies. In those projects, the trans shape was preferred by 3.3 kcal/mol, and it was inferred that a strong solvent effect was responsible for the gauche experimental conformations. In the QM work, a strong solvent effect is not needed to explain the preference for the gauche form because the trans shapes already have higher energy. A QM continuum model of aqueous solvation has only small effects on the torsional energy surface. The best rationalization of 24 values of the linkage torsion angles from small-molecule crystal structures is provided by HF/6-311++G**//B3LYP/6-31G* theory, a level that under-predicts the strength of hydrogen bonds.

Exploring the conformational energy landscape of glassy disaccharides by cross polarization magic angle spinning C13 nuclear magnetic resonance and numerical simulations. II. Enhanced molecular flexibility in amorphous trehalose

“…In the CHARMM27 force-field, the preferred conformational population gets closer to gauche conformations, which is evidently not consistent with the observed CPMAS spectrum. This conformational aspect of trehalose has already been long debated, and our observations are in agreement with the ab initio investigation of French et al [25]. One should, however, also reminds the suitability of the above reported force fields to simulate carbohydrates in a self-made matrix without solvent.…”

“…Nonetheless, it can be easily recognized that the most recent potential of mean force surface [27] and the previous quantum mechanical calculations at high level of theory [5,25] show that the conformation of the global minimum structure for the isolated trehalose molecule resides in the region of 50° < reported by Moyna and coworkers in form of three-dimensional plots [18,28]. However, it is enough clear from all the above discussed data that the gross features in the chemical shift of the populated region do not show significant changes, a fact that supports the independence of the (C 1 ,,) map from other structural details.…”

Molecular dynamics simulations and NMR spectroscopy studies of trehalose–lipid bilayer systems

“…Two key concepts relevant for these studies are the hydration process [21][22][23][24] and the conformational behavior of trehalose. [25][26][27] Many experimental and theoretical approaches have been employed to study membrane-sugar interactions. In particular, computer simulation is a powerful tool for investigations of the detailed picture of complex biological systems, and several studies of lipid bilayer-trehalose interactions have been reported using different degrees of sophistication for the interaction model.…”

Comparative performance of MM3(92) and two TINKER™ MM3 versions for the modeling of carbohydrates

“…On the other hand, the application of more rigorous methods were hindered by the rotameric complexity of the exo‐cyclic substituents (the “multiple minimum problem”2, 3), requiring several hundreds or thousands of minimizations for each structure 4. Therefore, although several DFT/ ab initio studies were carried out for monosaccharides,5–14 only a few were made for disaccharides or analogs 15–21. These larger structures were studied mostly by molecular mechanics using different force fields, with MM322, 23 being used for most of the systematic studies given its ability to handle directional hydrogen bonding and its parameterization of anomeric and exo ‐anomeric effects 3.…”