Juan-Luis Pascual-Ahuir

GEPOL: an improved description of molecular surfaces. III.: a new algorithm for the computation of a solvent-excluding surface

To understand and calculate the interactions of a solute with a solvent, a good method of computing the molecular surface is needed. Three kinds of surfaces may be used: the van der Waals Surface, the Accessible Surface, and the Molecular Surface. The latter is redefined in this article as the Solvent‐Excluding Surface. The new algorithm for computing the Solvent‐Excluding Surface included in the GEPOL93 program is described. GEPOL93 follows the same concept as former versions of GEPOL but with a full new algorithm. Thus, it computes the Solvent‐Excluding Surface by filling the spaces not accessible to the solvent with a set of new spheres. The computation is controlled by three parameters: the number of triangles per sphere, controlled by NDIV; the maximum overlap among the new spheres (OFAC); and the size of the smallest sphere that can be created (RMIN). The changes introduced for the computation of the ESURF make GEPOL93 not just a new version but a new program. An estimation is made of the error in the area and volume obtained in the function of the parameters.

Why is glycine a zwitterion in aqueous solution? A theoretical study of solvent stabilising factors

Abstract In this paper an ab initio study of specific and non-specific solvent effects on the glycine zwitterion energetics and formation mechanism is presented. Calculations are carried out at the HF an MP2 levels with the 6–31 + G ∗∗ basis set. The description of glycine in solution requires the use of continuum models or the inclusion of several discrete water solvent molecules into the calculations. Zwitterion formation in solution occurs by means of an intramolecular proton transfer from oxygen to nitrogen. An analysis of the intermolecular mechanism shows that the addition of one water molecule does not favour the process either geometrically or energetically.

Aminoacid zwitterions in solution: Geometric, energetic, and vibrational analysis using density functional theory-continuum model calculations

Glycine and alanine aminoacids chemistry in solution is explored using a hybrid three parameters density functional (B3PW91) together with a continuum model. Geometries, energies, and vibrational spectra of glycine and alanine zwitterions are studied at the B3PW91/6-31+G** level and the results compared with those obtained at the HF and MP2/6-31+G** levels. Solvents effects are incorporated by means of an ellipsoidal cavity model with a multipolar expansion (up to sixth order) of the solute’s electrostatic potential. Our results confirm the validity of the B3PW91 functional for studying aminoacid chemistry in solution. Taking into account the more favorable scaling behavior of density functional techniques with respect to correlated ab initio methods these studies could be extended to larger systems.

Continuum-uniform approach calculations of the solubility of hydrocarbons in water

Abstract The ransfer free energies from gas phase to water for some hydrocarbons are calculated by means of a continuum-uniform model of the solvent. For the calculation of the cavitation energy a model based on the surface tension is proposed. The calculated values are compared with the experimental free energies obtained with and without a corrective factor that accounts for the difference in the solute—solvent sizes. Good agreement between the theoretical free energies and the corrected experimental data is obtained. Our calculations seem to show that the hydrophobic effect is directly related to the molecular surface area.

A theoretical study of solvent effects on the conformational equilibria of neutral glycine in aqueous solution

Abstract In this work conformational equilibrium of neutral glycine in solution is systematically investigated by using DFT and MP2 methods combined with solvent continuum models. A systematic exploration of the potential energy surface and full geometry optimizations for several conformers have been carried out in the gas phase and aqueous solution at the MP2/6-31+G** and B3LYP/6-31+G** levels. Zero-point and thermal contributions to the free energy have been obtained at the B3LYP level. Both theoretical levels lead to very similar results, in geometrical and energetic terms, both in the gas phase and in solution. Solvent effects play an important role on the conformational equilibria of neutral glycine; so the absolute free energy minimum in solution is not the same as in the gas phase. The changes found when passing from gas phase to aqueous solutions can have important consequences also on the tautomeric equilibrium between the neutral and zwitterionic forms of glycine.

Modeling ?-lactam interactions in aqueous solution through combined quantum mechanics-molecular mechanics methods

In this article, we have carried out a series of theoretical computations intended to analyze the interactions of β‐lactam compounds in aqueous solution. The final aim is to rationalize the influence of the medium on β‐lactam antibiotics reactivity. In particular, the hydrolysis reaction has been studied because of the considerable interest due to its relationship with resistance mechanisms developed by bacteria. The study is extended to the simplest β‐lactam molecule, propiolactam or 2‐azetidinone, and to the corresponding hydroxylated complex (resulting from the addition of a hydroxyl anion to the carbonyl group) that plays a crucial role in hydrolysis processes. Molecular Dynamics simulations have been carried out using a hybrid quantum mechanics–molecular mechanics potential: the solute is described using the density functional theory, whereas water solvent molecules are treated classically. This represents a sophisticated computational level which, compared to usual force‐field simulations, has the advantage of allowing a detailed analysis of solutes electronic properties. The discussion of results is focused on the role played by solute–solvent hydrogen bonds and solvent fluctuations on solutes structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1401–1411, 1999

Reversibility and Diffusion in Mandelythiamin Decarboxylation. Searching Dynamical Effects in Decarboxylation Reactions

Decarboxylation of mandelylthiamin in aqueous solution is analyzed by means of quantum mechanics/molecular mechanics simulations including solvent effects. The free energy profile for the decarboxylation reaction was traced, assuming equilibrium solvation, while reaction trajectories allowed us to incorporate nonequilibrium effects due to the solvent degrees of freedom as well as to evaluate the rate of the diffusion process in competition with the backward reaction. Our calculations that reproduce the experimental rate constant show that decarboxylation takes place with a non-negligible free energy barrier for the backward reaction and that diffusion of carbon dioxide is very fast compared to the chemical step. According to these findings catalysts would not act by preventing the backward reaction.

A quantum mechanics/molecular mechanics study of the acylation reaction of TEM1 β-lactamase and penicillanate

The acylation step in β-lactamase catalyzed hydrolysis of β-lactams has been explored by means of a quantum mechanics/molecular mechanics approach (AM1/CHARMM). The TEM1 enzyme, a class A β-lactamase, and the penicillanate constitute the system employed in our study. The entire molecular system is divided into a quantum and a classical region: the quantum part is composed by the substrate, the serine Ser70 and the essential moieties of key active site residues, Lys73, Ser130 and Glu166, as well as a water molecule present in the active site region, while the classical part is formed by the remaining residues and structural waters of the enzyme. In particular, the sequence of steps proposed by Strynadka et al. (Nature, 1992, 359, 700) for the acylation reaction is analyzed. Minimal and transition structures for the mechanism are reported and an energy activation of 18.29 kcal mol−1 has been calculated for the rate-limiting step, the formation of an initial tetrahedral adduct. From this structure, two different mechanistic routes have been found to achieve the acyl–enzyme intermediate. In the first of them a simultaneous β-lactam ring opening and proton transfer from Ser130 to the β-lactam nitrogen atom occurs, presenting an energy barrier of 12.91 kcal mol−1 with respect to the tetrahedral intermediate. In the second route, these processes take place in a sequential way. From an energetic point of view, the sequential mechanism is favored, requiring the ring opening step (7.66 kcal mol−1) and the subsequent nitrogen protonation (2.76 kcal mol−1). Some reflections arising from the preference of sequential processes in this system are exposed.

Analysis of a concerted mechanism in β-lactam enzymatic hydrolysis. A quantum mechanics/molecular mechanics study

One of the postulated mechanisms for the acylation step in β-lactamase catalyzed hydrolysis of β-lactams, a concerted one, has been explored by means of a quantum mechanics/molecular mechanics approach. Minima and transition structures for the reaction path are reported. The TEM-1 enzyme, a class A β-lactamase, and a penicillanate, a substrate easily hydrolyzed by this enzyme, constitute the system employed in our study. We have also analyzed the effects of the protonation state of Lys73 on the reaction mechanism. The energy barriers obtained, too high for a catalytic process, indicate that a concerted mechanism is not the most probable enzymatic mechanism for the acylation. Useful information is obtained by comparing the enzyme structures corresponding to the protonated and the deprotonated Lys73 residue along the reaction path. In the protonated Michaelis complex the Glu166 residue appears considerably closer to the Lys73 residue than in the deprotonated structure. This fact implies that an initially protonated Lys73 could easily transfer a proton and thus would not be a factor in excluding acylation mechanisms in which Lys73 acts as the general base in the deprotonation of Ser70. On the other hand, the Lys73 deprotonated acyl–enzyme structure is in better agreement with the reported X-ray crystallographic data than that of the protonated case.

Correlation effects in proton transfer reactions in solution

Abstract The effects of correlation energy on proton transfer reactions in solution for [H 2 OHOH 2 ] + and [NH 3 HH 2 O] + systems have been studied. Solvent effects have been represented by means of a continuum model. The proton transfer energy profiles for fixed proton donor-proton acceptor distances have been obtained in the gas phase and in solution, both at the HF/6-311G ∗∗ and MP2/6-311G ∗∗ //HF levels of theory. Differences between the correlation energies calculated in the gas phase and in solution are negligible, showing that solvent effects can be correctly described for these proton transfer processes at the HF level.