Can current force fields reproduce ring puckering in 2-O-sulfo-α-l-iduronic acid? A molecular dynamics simulation study

The monosaccharide 2-O-sulfo-α-l-iduronic acid (IdoA2S) is one of the major components of glycosaminoglycans. The ability of molecular mechanics force fields to reproduce ring-puckering conformational equilibrium is important for the successful prediction of the free energies of interaction of these carbohydrates with proteins. Here we report unconstrained molecular dynamics simulations of IdoA2S monosaccharide that were carried out to investigate the ability of commonly used force fields to reproduce its ring conformational flexibility in aqueous solution. In particular, the distribution of ring conformer populations of IdoA2S was determined. The GROMOS96 force field with the SPC/E water potential can predict successfully the dominant skew-boat to chair conformational transition of the IdoA2S monosaccharide in aqueous solution. On the other hand, the GLYCAM06 force field with the TIP3P water potential sampled transitional conformations between the boat and chair forms. Simulations using the GROMOS96 force field showed no pseudorotational equilibrium fluctuations and hence no inter-conversion between the boat and twist boat ring conformers. Calculations of theoretical proton NMR coupling constants showed that the GROMOS96 force field can predict the skew-boat to chair conformational ratio in good agreement with the experiment, whereas GLYCAM06 shows worse agreement. The omega rotamer distribution about the C5–C6 bond was predicted by both force fields to have torsions around 10°, 190°, and 360°.

Conformational dynamics of HIV-1 protease: a comparative molecular dynamics simulation study with multiple amber force fields

Flap dynamics of HIV-1 protease (HIV-pr) controls the entry of inhibitors and substrates to the active site. Dynamical models from previous simulations are not all consistent with each other and not all are supported by the NMR results. In the present work, the er effect of force field on the dynamics of HIV-pr is investigated by MD simulations using three AMBER force fields ff99, ff99SB, and ff03. The generalized order parameters for amide backbone are calculated from the three force fields and compared with the NMR S2 values. We found that the ff99SB and ff03 force field calculated order parameters agree reasonably well with the NMR S2 values, whereas ff99 calculated values deviate most from the NMR order parameters. Stereochemical geometry of protein models from each force field also agrees well with the remarks from NMR S2 values. However, between ff99SB and ff03, there are several differences, most notably in the loop regions. It is found that these loops are, in general, more flexible in the ff03 force field. This results in a larger active site cavity in the simulation with the ff03 force field. The effect of this difference in computer-aided drug design against flexible receptors is discussed.

Development of complex classical force fields through force matching to ab initio data: Application to a room-temperature ionic liquid

Recent experimental neutron diffraction data and ab initio molecular dynamics simulation of the ionic liquid dimethylimidazolium chloride ([dmim]Cl) have provided a structural description of the system at the molecular level. However, partial radial distribution functions calculated from the latter, when compared to previous classical simulation results, highlight some limitations in the structural description offered by force fieldbased simulations. With the availability of ab initio data it is possible to improve the classical description of [dmim]Cl by using the force matching approach, and the strategy for fitting complex force fields in their original functional form is discussed. A self-consistent optimization method for the generation of classical potentials of general functional form is presented and applied, and a force field that better reproduces the observed first principles forces is obtained. When used in simulation, it predicts structural data which reproduces more faithfully that observed in the ab initio studies. Some possible refinements to the technique, its application, and the general suitability of common potential energy functions used within many ionic liquid force fields are discussed.

Studies in molecular dynamics: new criteria for evaluation of intramolecular force fields

The present thesis deals with some studies in molecular dynamics using spectroscopic data. Two new approximation procedures the variable method and the average bonding energy criterion have been developed for a reliable calculation of molecular force fields and applied to several molecular species belonging to the xy2 type.

Harmonic force fields from scaled SCF calculations: Program ASYM40

We report an extended version of our normal coordinate program ASYM40, which may be used to transform Cartesian force constants from ab initio calculations to a force field in nonredundant internal (symmetry) coordinates. When experimental data are available, scale factors for the theoretical force field may then be optimized by least-squares refinement. The alternative of refining an empirical force field to fit a wide variety of data, as with the previous version ASYM20, has been retained. We compare the results of least-squares refinement of the full harmonic force field with least-squares refinement of only the scale factors for an SCF calculated force field and conclude that the latter approach may be useful for large molecules where more sophisticated calculations are impractical. The refinement of scale factors for a theoretical force field is also useful when there are only limited spectroscopic data. The program will accept ab initio calculated force fields from any program that presents Cartesian force constants as output. The program is available through Quantum Chemistry Program Exchange.

Analytical potentials for triatomic molecules IX. The prediction of anharmonic force constants from potential energy surfaces based on harmonic force fields and dissociation energies for SO2 and O3

Analytical potential energy functions which are valid at all dissociation limits have been derived for the ground states of SO2 and O3. The procedure involves minimizing the errors between the observed vibrational spectra and spectra calculated by a variational procedure. Good agreement is obtained between the observed and calculated spectra for both molecules. Comparisons are made between anharmonic force fields, previously determined from the spectral data, and the force fields obtained by differentiating the derived analytical functions at the equilibrium configurations.

A model for stretch-bend interactions in molecular force fields

Interaction force constants between bond-stretching and angle-bending co-ordinates in polyatomic molecules have been attributed, by some authors, to changes of hybridization due to orbital-following of the bending co-ordinate, and consequent changes of bond length due to the change of hybridization. A method is described for using this model quantitatively to reduce the number of independent force constants in the potential function of a polyatomic molecule, by relating stretch-bend interaction constants to the corresponding diagonal stretching constants. It is proposed to call this model the Hybrid Orbital Force Field. The model is applied to the tetrahedral four co-ordinated carbon atom (as in methane) and to the trigonal planar three coordinated carbon atom (as in formaldehyde).

General derivative relations for anharmonic force fields

The brace notation, introduced by Allen and Csaszar (1993, J. chem. Phys., 98, 2983), provides a simple and compact way to deal with derivatives of arbitrary non-tensorial quantities. One of its main advantages is that it builds the permutational symmetry of the derivatives directly into the formalism. The brace notation is applied to formulate the general nth-order Cartesian derivatives of internal coordinates, and to provide closed forms for general, nth-order transformation equations of anharmonic force fields, expressed as Taylor series, from internal to Cartesian or normal coordinate spaces.

The calculation of force constants and normal coordinates III: constrained force fields for the methyl halides

A method is discussed for imposing any desired constraint on the force field obtained in a force constant refinement calculation. The application of this method to force constant refinement calculations for the methyl halide molecules is reported. All available data on the vibration frequencies, Coriolis interaction constants and centrifugal stretching constants of CH3X and CD3X molecules were used in the refinements, but despite this apparent abundance of data it was found that constraints were necessary in order to obtain a unique solution to the force field. The results of unconstrained calculations, and of three different constrained calculations, are reported in this paper. The constrained models reported are a Urey—Bradley force field, a modified valence force field, and a constraint based on orbital-following bond-hybridization arguments developed in the following paper. The results are discussed, and compared with previous results for these molecules. The third of the above models is found to reproduce the observed data better than either of the first two, and additional reasons are given for preferring this solution to the force field for the methyl halide molecules.

Chalcogenide-halides of niobium (V). 1. Gas-phase structures of NbOBr3, NbSBr3, and NbSCl3. 2. Matrix infrared spectra and vibrational force fields of NbOBr3, NbSBr3, NbSCl3, and NbOCl3

The molecular structures of NbOBr3, NbSCl3, and NbSBr3 have been determined by gas-phase electron diffraction (GED) at nozzle-tip temperatures of 250 degreesC, taking into account the possible presence of NbOCl3 as a contaminant in the NbSCl3 sample and NbOBr3 in the NbSBr3 sample. The experimental data are consistent with trigonal-pyramidal molecules having C-3v symmetry. Infrared spectra of molecules trapped in argon or nitrogen matrices were recorded and exhibit the characteristic fundamental stretching modes for C-3v species. Well resolved isotopic fine structure (Cl-35 and Cl-37) was observed for NbSCl3, and for NbOCl3 which occurred as an impurity in the NbSCl3 spectra. Quantum mechanical calculations of the structures and vibrational frequencies of the four YNbX3 molecules (Y = O, S; X = Cl, Br) were carried out at several levels of theory, most importantly B3LYP DFT with either the Stuttgart RSC ECP or Hay-Wadt (n + 1) ECP VDZ basis set for Nb and the 6-311 G* basis set for the nonmetal atoms. Theoretical values for the bond lengths are 0.01-0.04 Angstrom longer than the experimental ones of type r(a), in accord with general experience, but the bond angles with theoretical minus experimental differences of only 1.0-1.5degrees are notably accurate. Symmetrized force fields were also calculated. The experimental bond lengths (r(g)/Angstrom) and angles (angle(alpha)/deg) with estimated 2sigma uncertainties from GED are as follows. NbOBr3: r(Nb=O) = 1.694(7), r(Nb-Br) = 2.429(2), angle(O=Nb-Br) = 107.3(5), angle(Br-Nb-Br) = 111.5(5). NbSBr3: r(Nb=S) = 2.134(10), r(Nb-Br) = 2.408(4), angle(S=Nb-Br) = 106.6(7), angle(Br-Nb-Br) = 112.2(6). NbSCl3: Nb=S) = 2.120(10), r(Nb-Cl) = 2.271(6), angle(S=Nb-Cl) = 107.8(12), angle(Cl-Nb-Cl) = 111.1(11).