Carles Colominas

Cavitation contribution to the free energy of solvation.: Comparison of different formalisms in the context of MST calculations

Abstract We present a systematic study on the contribution of the cavitation term to the solvation free energy of a series of small neutral molecules. Different approaches to the calculation of the cavitation term in MST–SCRF calculations of the solvation free energy are analyzed. Optimum van der Waals parameters to be used with different definitions of cavitation contributions are obtained for water, chloroform and carbon tetrachloride.

Theoretical determination of the solvation free energy in water and chloroform of the nucleic acid bases

Abstract The free energy of solvation in H 2 O and CHCl 3 of the N -methyl derivatives of the five nucleic acid bases has been determined from self-consistent reaction field (SCRF) calculations and free energy perturbation (FEP)_simulations. Theoretical estimates of the respective water/chloroform partition coefficients (log P ) were determined from the solvation free energies in the two solvents. Comparison of the results with experimental data suggests a reliable estimation of the free energies of solvation for the nucleic acid bases.

MONTE CARLO-MST : NEW STRATEGY FOR REPRESENTATION OF SOLVENT CONFIGURATIONAL SPACE IN SOLUTION

A new procedure for the representation of the configurational space of solutes in solution is presented. The method is based on the combination of standard Monte Carlo techniques with the continuum model developed by the Pisa group in its semiclassical version, which was developed by our group. The suitability of the method for exploring the configurational space of chemical systems in solution has been tested by analyzing the dimers of formic acid, imidazole, and benzene, as well as the interaction between the ammonium cation and the formate anion. The results in aqueous solution are compared with those obtained in a gas phase environment. The calculations provide detailed information on the interaction modes between monomers and their contribution to the dimer. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 665–678, 1999

Prediction of Conformational Free Energy Differences of Solutes in Solution∶ An MC-MST Study

This study reports an extension of the MC-MST method to explore the conformational space of molecules in condensed phases. The MC-MST method combines a Monte Carlo (MC) Metropolis algorithm to sample the conformational space with the semiclassical version of the Miertus-Scrocco-Tomasi (MST) continuum model to treat solvation effects. The extension of the MC-MST method to describe the solvent-induced changes in the conformational space is examined for 1,2-dichloroethane and the two tautomers of neutral histamine. The results allow us to discuss the capabilities of the MC-MST method to reproduce the conformational preferences of molecules in solution.

Conformational folding induced by π–π interaction in a series of flexible dyads consisting of isomeric mesoporphyrin nitrobenzyl esters

A, series of isomeric (ortho, meta and para) nitrobenzyl mono- and di-esters of mesoporphyrin, in which the nitrobenzyl group(s) is (are) mono-linked through one or both propionate chains of the porphyrin, have been synthesized and their room-temperature conformations in a number of solvents have been investigated using 1H NMR spectroscopy and theoretical calculations. Folding of these flexible dyads is consistent with the following observations: (1)1H NMR ring current upfield shift in all solvents assayed [i.e., CDCl3, CDCl3–CD3OD (10:1) and C6D6] of 0.5–2.5 ppm for the aryl protons; (2) these shifts are independent of temperature over the range 25 to –55 °C; (3) the 1H NMR resonance values of mesoporphyrin benzyl ester (lacking the nitro group) are not shifted, indicating a preferred, sterically less crowded, extended conformation. The presence of the nitro group on the phenyl ring(s) is responsible for the folding of these flexible dyads, and the results can be interpreted in terms of π–π interactions (C. A. Hunter and J. K. M. Sanders, J. Am. Chem. Soc., 1990, 112, 5525–5534) between the two halves. In the theoretically calculated (molecular mechanics and semiempirical calculations) minimum-energy folded conformations, each benzyl group lies approximately parallel to the porphyrin π-system with its centre slightly offset relative to the centre of the porphyrin; however, for each isomer, significant structural differences between the ortho isomer and its meta and para counterparts are found. The implications of these differences for the photoinduced electron transfer efficiencies in these dyads are discussed.

CYCLIZATION OF 1,5-DINITRILE SYSTEMS WITH HYDROGEN HALIDES : A SEARCH FOR THE UNDETECTED KEY TAUTOMER

Abstract The 13 C NMR spectra of the pyridones 7a-d recorded in DMSO-d 6 show three groups of signals which correspond to the two diastereomers of the 7-exo tautomer and the 7-endo tautomer. The X-ray powder analysis and the molecular structures of 7a-c clearly prove that these compounds, and probably 7d , are present in the solid state as a single diastereomer of the 7-exo tautomer which, on being dissolved, establishes an equilibrium with the other diastereomer through the 7-endo tautomer. This later had been proposed as a key intermediate in the cyclization of the 1,5-dinitrile system present in 7a-d but was not previously detected.

On the Use of SCRF Methods in Drug Design Studies

Self consistent reaction field (SCRF) methods have been largely used to examine solvent effects in chemical interactions. These methods’ are designed to determine solvation free energy, which is the reversible work necessary to transfer a molecule from gas phase to solution (considering the same reference states, typically 1M). In SCRF methods such a work is computed (see Eq. 1) as the addition of three elemental contributions: i) the work necessary to build up the solute cavity in the solvent (cavitation term), ii) the work needed to generate the uncharged solute in the pre-formed cavity (van der Waals term), and iii) the work spent in generating the solute charge distribution in solution (the electrostatic term).