Conformation of the C-5/C-6 fragment of aldohexopyranoses

Molecular dynamics simulations of native α-, β-, and γ-cyclodextrin in aqueous solution have been conducted with the goal to investigate the performance of the CHARMM36 force field, the AMBER-compatible q4md-CD force field, and five variants of the GROMOS force field. The properties analyzed are structural parameters derived from X-ray diffraction and NMR experiments as well as hydrogen bonds and hydration patterns, including hydration free enthalpies. Recent revisions of the torsional-angle parameters for carbohydrate systems within the GROMOS family of force fields lead to a significant improvement of the agreement between simulated and experimental NMR data. Therefore, we recommend using the variant 53A6GLYC instead of 53A6 and 56A6CARBO_R or 2016H66 instead of 56A6CARBO to simulate cyclodextrins in solution. The CHARMM36 and q4md-CD force fields show a similar performance as the three recommended GROMOS parameter sets. A significant difference is the more flexible nature of the cyclodextrins modeled w...

Validation and Comparison of Force Fields for Native Cyclodextrins in Aqueous Solution

Complexation process of amylose under different concentrations of linoleic acid using molecular dynamics simulation.

The parameterization of torsional/dihedral angle potential energy terms is a crucial part of developing molecular mechanics force fields Quantum mechanical (QM) methods are often used to provide samples of the potential energy surface (PES) for fitting the empirical parameters in these force field terms To ensure that the sampled molecular configurations are thermodynamically feasible, constrained QM geometry optimizations are typically carried out, which relax the orthogonal degrees of freedom while fixing the target torsion angle(s) on a grid of values However, the quality of results and computational cost are affected by various factors on a non-trivial PES, such as dependence on the chosen scan direction and the lack of efficient approaches to integrate results started from multiple initial guesses In this paper, we propose a systematic and versatile workflow called TorsionDrive to generate energy-minimized structures on a grid of torsion constraints by means of a recursive wavefront propagation algorithm, which resolves the deficiencies of conventional scanning approaches and generates higher quality QM data for force field development The capabilities of our method are presented for multi-dimensional scans and multiple initial guess structures, and an integration with the MolSSI QCArchive distributed computing ecosystem is described The method is implemented in an open-source software package that is compatible with many QM software packages and energy minimization codes

Driving torsion scans with wavefront propagation.

An extension of the GROMOS 56a6CARBO/CARBO_R force field for hexopyranose-based carbohydrates is presented. The additional parameters describe the conformational properties of uronate residues. The three distinct chemical states of the carboxyl group are considered: deprotonated (negatively charged), protonated (neutral), and esterified (neutral). The parametrization procedure was based on quantum-chemical calculations, and the resulting parameters were tested in the context of (i) flexibility of the pyranose rings under different pH conditions, (ii) conformation of the glycosidic linkage of the (1 → 4)-type for uronates with different chemical states of carboxyl moieties, (iii) conformation of the exocyclic (i.e., carboxylate and lactol) moieties, and (iv) structure of the Ca2+-linked chain–chain complexes of uronates. The presently proposed parameters in combination with the 56a6CARBO/CARBO_R set can be used to describe the naturally occurring polyuronates, composed either of homogeneous (e.g., glucuron...

Extension of the GROMOS 56a6CARBO/CARBO_R Force Field for Charged, Protonated, and Esterified Uronates.

Intramolecular hydrogen-bonding (H-bonding) is commonly regarded as a major determinant of the conformation of (bio)molecules. However, in an aqueous environment, solvent-exposed H-bonds are likely to represent only a marginal (possibly adverse) conformational driving as well as steering force. For example, the hydroxymethyl rotamers of glucose and galactose permitting the formation of an intramolecular H-bond with the adjacent hydroxyl group are not favored in water but, in the opposite, least populated. This is because the solvent-exposed H-bond is dielectrically screened as well as subject to intense H-bonding competition by the water molecules. In the present study, the effect of a decrease in the solvent polarity on this rotameric equilibrium is probed using molecular dynamics simulation. This is done by considering six physical solvents (H2O, DMSO, MeOH, CHCl3, CCl4, and vacuum), along with 19 artificial water-like solvent models for which the dielectric permittivity and H-bonding capacity can be modulated independently via a scaling of the O–H distance and of the atomic partial charges. In the high polarity solvents, the intramolecular H-bond is observed, but arises as an opportunistic consequence of the proximity of the H-bonding partners in a given rotameric state. Only when the polarity of the solvent is decreased does the intramolecular H-bond start to induce a conformational pressure on the rotameric equilibrium. The artificial solvent series also reveals that the effects of the solvent permittivity and of its H-bonding capacity mutually enhance each other, with a slightly larger influence of the permittivity. The hydroxymethyl conformation in hexopyranoses appears to be particularly sensitive to solvent-polarity effects because the H-bond involving the hydroxymethyl group is only one out of up to five H-bonds capable of forming a network around the ring.

Solvent-Modulated Influence of Intramolecular Hydrogen-Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study

Pavel Oborský

Papers

Solvent-Modulated Influence of Intramolecular Hydrogen-Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study