The first hyperpolarizability of p-nitroaniline in 1,4-dioxane:A quantum mechanical/molecular mechanics study

In this work we have investigated the first hyperpolarizability of pNA in 1,4-dioxane solution using a quantum mechanics/molecular mechanics (QM/MM) model. The particular model adopted is the recently developed discrete solvent reaction field (DRF) model. The DRF model is a polarizable QM/MM model in which the QM part is treated using time-dependent density-functional theory and local-field effects are incorporated. This allows for direct computation of molecular effective properties which can be compared with experimental results. The solvation shift for the first hyperpolarizability is calculated to be 30% which is in good agreement with the experimental results. However, the calculated values, both in the gas phase and in solution, are by a factor of 2 larger than the experimental ones. This is in contrast to the calculation of the first hyperpolarizability for several small molecules in the gas phase where fair agreement is found with experimental. The inclusion of local-field effects in the calculations was found to be crucial and neglecting them led to results which are significantly larger. To test the DRF model the refractive index of liquid 1,4-dioxane was also calculated and found to be in good agreement with experiment. (c) 2005 American Institute of Physics

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

This study reports in detail the results of systematic large-scale theoretical investigations of the acidic dimeric structural units (D-E, E-F, F-G, and G-H) and pentamer D-E-F-G-H (fondaparinux) of the glycosaminoglycan heparin, and their anionic forms. The geometries and energies of these oligomers have been computed using HF/6-31G(d), Becke3LYP/6-31G(d), and Becke3LYP/6-311+G(d,p) methods. The optimized geometries indicate that the most stable structure of these units in the neutral state is stabilized via a system of intramolecular hydrogen bonds. The equilibrium structure of these species changed appreciably upon dissociation. Water has a remarkable effect on the geometry of the anions studied. Because of high negative charge, the solvent effect also resulted in an appreciable energetic stabilization of biologically active anionic forms of these glycosaminoglycans. The stable energy conformations around glycosidic bonds found for dimers and pentamer investigated are compared and discussed with the available experimental X-ray structural data for the structurally related heparin-derived pentasaccharides in cocrystals with proteins

On the inactivity of thiol-subtilisin:The role of the intramolecular electric field

Based on computed proton affinities for several model systems, the energetics of proton transfer and the acidity of the catalytic triads Cys-His-Asn (papain). Cys-His-Asp (thiol-subtilisin) and Ser-His-Asp (subtilisin) are discussed. It is shown that in papain the ion-pair Cys−-HisH+ exists owing to the intramolecular electric field, and that a similar situation is found in thiol-subtilisin. but not in subtilisin. Assuming similar reaction mechanisms for papain and thiol-subtilisin - i.e. proton transfer from HisH+ to the NH group of the scissile peptide bond - the inactivity of thil-subtilisin towards proteins is explained by the much greater basicity of His in the complex His-Asp− than in His-Asn. In order for this explanation to be consistent, it is tentatively concluded that the catalytic mechanism of the serine proteases is different from that of the cystein proteases, and involves direct transfer of the serine proton to the leaving group in the acylation step

Quantum Chemistry and Enzymes

Structured macromolecules such as proteins have intramolecular electric fields of considerable strength. Sources of such fields may be ionizable groups, but also the protein backbone contributes, particularly when α-helices are present. The fields cause shifts in the physico-chemical properties of, e.g., active site residues of enzymes, which may confuse the interpretation of observed properties. Since such fields are not open to direct experimental measurement, quantum mechanical calculations may be the only way to investigate these fields and their effects. Here, we discuss the results of ab initio molecular orbital calculations describing the effect of static fields on the active sites of subtilisin, papain, and thiol-subtilisin. Our conclusion is that quantum chemistry can provide additional and independent evidence about many aspects of molecular catalysis

DRF90: a polarizable force field

The direct reaction field (DRF) approach has proven to be a useful tool to investigate the influence of solvents on the quantum/classical behaviour of solute molecules. In this paper, we report the latest extension of this DRF approach, which consists of the gradient of the completely classical energy expressions of this otherwise QM/MM method. They can be used in (completely classical) molecular dynamics (MD) simulations and geometry optimizations, that can be followed by a number of single point QM/MM calculations on configurations obtained in these simulations/optimizations. We report all energy and gradient expressions, and results for a number of interesting (model) systems. They include geometry optimization of the benzene dimer as well as MD simulations of some solvents. The most stable configuration for the benzene dimer is shown to be the parallel-displaced form, which is slightly more stable (0.3 kcal/mol) than the T-shaped dimer