Estanislao Silla

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.

Molecular volumes and surfaces of biomacromolecules via GEPOL: a fast and efficient algorithm

A triangular tesselation approach to build up surfaces has been adapted to the study of biomolecules. By using a data-coded generic pentakisdodecahedron each atom is assigned a particular sphere whose radii are chosen according to any suitable property. Different types of surfaces have been adapted to this method: van der Waals, surface accessible, and Richards molecular surface. A simple method is used to eliminate all triangles found at the intersection volume of the atomic spheres and a fast algorithm is employed to calculate the area of the envelope surface and the volume therein. The data about the surface are given by the coordinates of the center of each triangle, elementary surface value, and vector coordinates of the normal to the surface. Color coding of standard properties such as charge densities, potential energy, or any scalar property can be easily done with standard graphics libraries. Fairly detailed information on vector properties, such as electric field and atom velocity, can also be graphically represented by using projections along the normals with adequate color coding.

Theoretical insights in enzyme catalysis

In this tutorial review we show how the methods and techniques of computational chemistry have been applied to the understanding of the physical basis of the rate enhancement of chemical reactions by enzymes. This is to answer the question: Why is the activation free energy in enzyme catalysed reactions smaller than the activation free energy observed in solution? Two important points of view are presented: Transition State (TS) theories and Michaelis Complex (MC) theories. After reviewing some of the most popular computational methods employed, we analyse two particular enzymatic reactions: the conversion of chorismate to prephenate catalysed by Bacillus subtilis chorismate mutase, and a methyl transfer from S-adenosylmethionine to catecholate catalysed by catechol O-methyltransferase. The results and conclusions obtained by different authors on these two systems, supporting either TS stabilisation or substrate preorganization, are presented and compared. Finally we try to give a unified view, where a preorganized enzyme active site, prepared to stabilise the TS, also favours those reactive conformations geometrically closer to the TS.

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.

On the tautomerization process of glycine in aqueous solution

The experimental activation energy for the tautomerization of glycine zwitterion neutral form has been reported to be 14.6 kcalrmol. It has been generally assumed that this energy barrier is needed for proton transfer to occur. However, previous theoretical results do not support this interpretation. In the present work, we examine this question using density functional calculations, extended basis sets and a polarizable continuum solvent model. Our results suggest that the limiting step for the tautomerization process corresponds basically to H-atom reorientation in the -COOH group. This could be a general feature in the tautomerization of amino acids. q 2000 Elsevier Science B.V. All rights reserved.

Mechanism and plasticity of isochorismate pyruvate lyase: a computational study.

The isochorismate pyruvate lyase (IPL) from Pseudomonas aeruginosa, designated as PchB, catalyzes the transformation of isochorismate into pyruvate and salicylate, but it also catalyzes the rearrangement of chorismate into prephenate, suggesting that both reactions may proceed by a pericyclic mechanism. In this work, molecular dynamics simulations employing hybrid quantum mechanics/molecular mechanics methods have been carried out to get a detailed knowledge of the reaction mechanism of PchB. The results provide a theoretical rate constant enhancement by comparison with the reaction in solution, in agreement with the experimental data, and confirm the pericyclic nature of the reaction mechanism. The robustness of this promiscuous enzyme has been checked by considering the impact of Ala37Ile mutation, previously proposed by us to improve the secondary chorismate mutase (CM) activity. The effect of this mutation, which was shown to increase the rate constant for the CM activity by a factor of 10(3), also increases the IPL catalytic efficiency, although only by a factor of 6.

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.

Predicting an Improvement of Secondary Catalytic Activity of Promiscuos Isochorismate Pyruvate Lyase by Computational Design

Improvement of the secondary catalytic activity of promiscuous enzymes can be guided by computational protein engineering. This methodology has been applied to isochorismate pyruvate lyase (IPL) that catalyzes isochorismate transformation into pyruvate and salicylate but it also presents secondary activity catalyzing the transformation of chorismate into prephenate. According to the computational results, a mutation of Val by Ile at position 38 would keep the enol pyruvyl moiety of the substrate in a diaxial conformation, closer to the TS geometry, thus reducing the free energy barrier of the chemical reaction 4.4 kcal·mol-1 with respect to the native IPL.

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.