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 m…

Molecular surface area and hydrophobic effect.

Calculation of binding energy using BLYP/MM for the HIV-1 integrase complexed with the S-1360 and two analogues.

Abstract Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. S-1360 is a potent and selective inhibitor of HIV-1 IN. In this work, we have carried out molecular dynamics (MD) simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) approach, to determine the protein–ligand interaction energy for S-1360 and two analogues. Analysis of the MD trajectories reveals that the strongest protein–inhibitor interactions, observed in the three studied complexes, are established with Lys-159 residue and Mg 2+ cation. Calculations of binding energy using BLYP/MM level of theory reveal that there is a direct rela…

Calculation of the relative basicities of methylamines in solution

Abstract The relative basicities in solution of the methylamines have been calculated using the model of Miertus, Scrocco and Tomasi to describe the solvent effect. The surface of the cavity is defined with the GEPOL method. The ab initio calculations have been performed using a 4-31G basis set. The relative order is reproduced using a combination of the gas-phase proton affinities obtained with quantum-mechanical methods by Eades, Weil, Dixon and Douglass and the solvation values obtained by us. The results seem to point out that the irregular order is not due to solvent but to basis-set effects.

Water-Assisted Alkaline Hydrolysis of Monobactams: A Theoretical Study

A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out at the B3LYP/6-31+G* level. The effect of bulk solvent is taken into account using the PCM solvation model while specific solvent effects are represented by the inclusion of an ancillary water molecule along the reaction profile. The calculated free energy barriers in solution are in reasonable agreement with experimental values. The observed substituent effects due to the presence of the 3-formylamino and the SO(3) groups attached to the beta-lactam ring are crucial factors determining the hydrolysis of monobactam antibioti…

Molecular dynamics simulation in aqueous solution of N -methylazetidinone as a model of β -lactam antibiotics

In this article, we analyze the results of a molecular dynamics simulation in aqueous solution of the N-methylazetidinone molecule, often used to model β-lactam antibiotics. The radial distribution functions (RDFs) corresponding to the most interesting atoms, in terms of reactivity, are presented. We focus our study on the effect of a polar environment on the molecule. The solvent structure around the system is compared to the structure of β-lactam-water complexes, as obtained in a previous study of reaction mechanisms for the neutral and alkaline hydrolyses of N-methylazetidinone. Two types of complexes have been considered which are related to different hydrolysis mechanisms having simila…

Computational design of biological catalysts

The purpose of this tutorial review is to illustrate the way to design new and powerful catalysts. The first possibility to get a biological catalyst for a given chemical process is to use existing enzymes that catalyze related reactions. The second possibility is the use of immune systems that recognize stable molecules resembling the transition structure of the target reaction. We finally show how computational techniques are able to provide an enormous quantity of information, providing clues to guide the development of new biological catalysts

Preorganization and reorganization as related factors in enzyme catalysis: the chorismate mutase case.

In this paper a deeper insight into the chorismate-to prephenate-rearrangement, catalyzed by Bacillus subtilis chorismate mutase, is provided by means of a combination of statistical quantum mechanics/molecular mechanics simulation methods and hybrid potential energy surface exploration techniques. The main aim of this work is to present an estimation of the preorganization and reorganization terms of the enzyme catalytic rate enhancement. To analyze the first of these, we have studied different conformational equilibria of chorismate in aqueous solution and in the enzyme active site. Our conclusion is that chorismate mutase preferentially binds the reactive conformer of the substrate--that…

Molecular surface calculations on organic compounds

Abstract The molecular surface area was calculated for 82 hydrocarbons, esters, ethers, alcohols and ketones including linear, branched and cyclic ones. The relationship between the aqueous solubility and the molecular surface area was determined for each family of compounds and for all the families together. The results show that solubility is mainly determined by molecular surface area and that the influence of functional group is the same for all the oxygen containing compounds studied.

Electrostatic interaction of a solute with a continuum. Improved description of the cavity and of the surface cavity bound charge distribution.

Algorithms for a finer description of cavities in continuous media and for a more efficient selection of sampling points on the cavity surface are described. Applications to the evaluation of solute surface and volume and to the calculation of the solute-solvent electrostatic interaction energy, as well as of the cavitation energy are shown as examples.

The solvent-excluding surface as a descriptor of ionic channels: Gramicidin-A

Abstract We have set out a methodology for checking the performance of the methods used to compute the Solvent-Excluding Surface. The method consists of computing the area of the Solvent-Excluding Surface of a model of channel, with a fixed pore size, for several values of the solvent radius. The graphical representation of the value of the area versus the radius of the solvent sphere shows a sharp change just at the radius of the pore. With this model we may analyze the ability of each method to describe small changes of the surface. We made the study with GEPOL93, older versions of GEPOL and MSDOT. The study is applied to a natural protein channel, as is Gramicidin-A, showing that this ty…

Enzymatic effects on reactant and transition states. The case of chalcone isomerase.

Chalcone isomerase catalyzes the transformation of chalcone to naringerin as a part of flavonoid biosynthetic pathways. The global reaction takes place through a conformational change of the substrate followed by chemical reaction, being thus an excellent example to analyze current theories about enzyme catalysis. We here present a detailed theoretical study of the enzymatic action on the conformational pre-equilibria and on the chemical steps for two different substrates of this enzyme. Free-energy profiles are obtained in terms of potentials of mean force using hybrid quantum mechanics/molecular mechanics potentials. The role of the enzyme becomes clear when compared to the counterpart eq…

GEPOL: An improved description of molecular surfaces. I. Building the spherical surface set

The algorithm used by the program GEPOL to compute the Molecular Surface (MS), as defined by Richards, is presented in detail. GEPOL starts like other algorithms from a set of spheres with van der Waals radii, centered on the atoms or group of atoms of the molecule. GEPOL computes the MS by first searching the spaces inaccessible to the solvent and consequently filling them with a new set of spheres. Here we study the behavior of the method with its parameters, presenting several examples of application.

A QM/MM study of the reaction mechanism for the 3′-processing step catalyzed by HIV-1 integrase

Integrase (IN) is one of the three human immunodeficiency virus type 1 enzymes (HIV-1) essential for effective viral replication. This viral enzyme is involved in the integration of HIV DNA into host chromosomal DNA. In this work we have carried out molecular dynamics simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) approach to study the reaction mechanism for the 3′-processing step of DNA integration using a model substrate. The results obtained by QM(AM1)/MM and QM(PM3)/MM simulations have been improved by single-point corrections using an ab initio method to describe the quantum subsystem. The results obtained within this computational model can be used to obtain …

A quantum mechanics/molecular mechanics study of the protein-ligand interaction for inhibitors of HIV-1 integrase.

Human immunodeficiency virus type-1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Diketo acids such as L-731,988 and S-1360 are potent and selective inhibitors of HIV-1 IN. In this study, we used molecular dynamics simulations, within the hybrid quantum mechanics/molecular mechanics (QM/MM) approach, to determine the protein-ligand interaction energy between HIV-1 IN and L-731,988 and 10 of its derivatives and analogues. This hybrid methodology has the advantage that it includes quantum effects such as ligand polarisation upon binding, which can be very important when highly polarisable groups are embedded in anisotropic environments, as for example in metal-c…

Amino Acid Chemistry in Solution:  Structural Study and Vibrational Dynamics of Glutamine in Solution. An ab Initio Reaction Field Model

The self-consistent reaction field (SCRF) theory was used to study structural and vibrational features of the amino acid L-glutamine in solution. Raman and infrared spectra of this molecule in solutions of H 2O and D2O were recorded and measured. The bands were firstly assigned on the basis of the isotopic shifts. An ab initio quadratic force field at the 6-31 +G* level was achieved. The calculation simulated a polar solvent by placing the molecule in an ellipsoidal cavity surrounded by a continuum dielectric. The theoretical results, in terms of structural parameters, vibrational frequencies and descriptions, and infrared intensities, were in satisfactory agreement with the experimental da…

FUNDAMENTAL PRINCIPLES GOVERNING SOLVENTS USE

A Computational Study of the Protein-Ligand Interactions in CDK2 Inhibitors: Using Quantum Mechanics/Molecular Mechanics Interaction Energy as a Predictor of the Biological Activity

ABSTRACT: We report a combined quantum mechanics/molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (cyclin-dependent kinase 2) and five inhibitors with the N2 -substituted 6-cyclohexylmethoxypurine scaffold. The computational results in this work show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before to our knowledge. The computed interaction …

Hybrid Quantum Mechanics/Molecular Mechanics Simulations with Two-Dimensional Interpolated Corrections:  Application to Enzymatic Processes

Hybrid quantum mechanics/molecular mechanics (QM/MM) techniques are widely used to study chemical reactions in large systems. Because of the computational cost associated with the high dimensionality of these systems, the quantum description is usually restricted to low-level methods, such as semiempirical Hamiltonians. In some cases, the description obtained at this computational level is quite poor and corrections must be considered. We here propose a simple but efficient way to include higher-level corrections to be used in potential energy surface explorations and in the calculation of potentials of mean force. We evaluate a correction energy term as the difference between a high-level …

Internal rotation of 1,2-dichloroethane in haloalkane dehalogenase. A test case for analyzing electrostatic effects in enzymes

1,2-Dichoroethane (DCE) is a prototypical molecule for studying electrostatic solvent effects on molecular conformation as far as rotation around the carbon−carbon bond notably changes the electric...

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:…

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 …

GEPOL: An improved description of molecular surfaces II. Computing the molecular area and volume

The algorithm used by the program GEPOL for a finer description of molecular surface (for a fast calculation of molecular area and volume and for an efficient selection of sampling points) is presented in detail. Different types of surfaces such as van der Waals and Richard's molecular surfaces can be computed. As we described in the first article (J.L. Pascual-Ahuir and E. Silla, J. Comp. Chem., 11, 1047(1990)), GEPOL begins by building a set of spherical surfaces which fill the space which is not solvent accessible. In this second article, a triangular tessellation approach to select the parts of these spherical surfaces which form the molecular surface is described. By using a data coded…

Conformational equilibrium of chorismate. A QM/MM theoretical study combining statistical simulations and geometry optimisations in gas phase and in aqueous solution

We report a theoretical study on the conformational equilibrium of chorismate that precedes its rearrangement to prephenate, an important enzyme-catalyzed reaction. In first place we show that the usual classification of chorismate conformers based on the relative position of the hydroxyl and ether bridge, pseudo-diaxial and pseudo-diequatorial, is not the only relevant factor from the point of view of the a posteriori rearrangement. Here we also analyse another complementary geometrical classification based on the interatomic distance between the carbon atoms to be bounded. Using the umbrella sampling approach and this distance as distinguished internal reaction coordinate, the gas phase A…

Dependence of enzyme reaction mechanism on protonation state of titratable residues and QM level description: lactate dehydrogenase

We have studied the dependence of the chemical reaction mechanism of L-lactate dehydrogenase (LDH) on the protonation state of titratable residues and on the level of the quantum mechanical (QM) description by means of hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods; this methodology has allowed clarification of the timing of the hydride transfer and proton transfer components that hitherto had not been possible to state definitively. Ferrer Castillo, Silvia, Silvia.Ferrer@uv.es, Silla Santos, Estanislao, Estanislao.Silla@uv.es ; Tuñon Garcia de Vicuña, Ignacio Nilo, Ignacio.Tunon@uv.es

Towards a Rational Design of Antibody Catalysts through Computational Chemistry

A density functional study of flavonoid compounds with anti-HIV activity.

Abstract Quantum chemical calculations at the DFT/B3LYP theory level, with the 6-31G* basis set, was employed to calculate a set of molecular properties of 26 flavonoid compounds with anti-HIV activity. The correlation between biological activity and structural properties was obtained by using the multiple linear regression method. The model obtained showed not only statistical significance but also predictive ability. We demonstrate in this paper that the anti-HIV activity of compounds can be related with the molecular hydrophobicity (ClogP), the electronegativity ( χ ) and the charges on some key atoms, while that the toxicity can be related with the electronic affinities (EA), ClogP and …

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 Richard's 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…

A quantum mechanics-molecular mechanics study of dissociative electron transfer : The methylchloride radical anion in aqueous solution

The dissociative electron transfer reaction CH3Cl+e−→CH3•+Cl− in aqueous solution is studied by using a QM/MM method. In this work the quantum subsystem (a methylchloride molecule plus an electron) is described using density functional theory while the solvent (300 water molecules) is described using the TIP3P classical potential. By means of molecular dynamics simulations and the thermodynamic integration technique we obtained the potential of mean force (PMF) for the carbon–chlorine bond dissociation of the neutral and radical anion species. Combining these two free energy curves we found a quadratic dependence of the activation free energy on the reaction free energy in agreement with Ma…

ChemInform Abstract: Computational Design of Biological Catalysts

The purpose of this tutorial review is to illustrate the way to design new and powerful catalysts. The first possibility to get a biological catalyst for a given chemical process is to use existing enzymes that catalyze related reactions. The second possibility is the use of immune systems that recognize stable molecules resembling the transition structure of the target reaction. We finally show how computational techniques are able to provide an enormous quantity of information, providing clues to guide the development of new biological catalysts.

Theoretical study of stationary structures of acetamidine unimolecular decomposition

Abstract The unimolecular decomposition of acetamidine to ammonia and acetonitrile was examined by ab initio methods. Stationary points, i.e. the reactant, product and transition structures, have been characterized. The process has an asynchronous mechanism, the transition state being described as a four-membered ring. To establish the relevance of different basis sets, calculations with eight standard Gaussian basis sets, STO-3G, 3-21G, 4-21G, 4-31G, 6-31G, 6-311G, 6-31G*, and G-31G**, were carried out.

Theoretical Study of Catalytic Efficiency of a Diels–Alderase Catalytic Antibody: An Indirect Effect Produced During the Maturation Process

The Diels–Alder reaction is one of the most important and versatile transformations available to organic chemists for the construction of complex natural products, therapeutics agents, and synthetic materials. Given the lack of efficient enzymes capable of catalyzing this kind of reaction, it is of interest to ask whether a biological catalyst could be designed from an antibody-combining site. In the present work, a theoretical study of the different behavior of a germline catalytic antibody (CA) and its matured form, 39 A-11, that catalyze a Diels–Alder reaction has been carried out. A free-energy perturbation technique based on a hybrid quantum-mechanics/molecular-mechanics scheme, togeth…

Amino acid chemistry in solution: structural properties and vibrational dynamics of serine using density functional theory and a continuum solvent model

A structural and vibrational study of amino acid serine in aqueous solution has been carried out using Fourier transform spectroscopies and quantum mechanical calculations. FT-IR and FT-Raman spectra of serine in H2O and D2O solutions were recorded and a general assignment of the observed bands was proposed on the basis of a zwitterionic structure for serine. Main criteria were the observed wavenumber shifts upon deuteration and previous assignments for other amino acids. A quadratic force field was computed using ab initio methodology at the 6-31+G** level and the hybrid functional B3LYP. The solvent effect was simulated by placing the serine molecule into an ellipsoidal cavity surrounded …

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

Transition structure selectivity in enzyme catalysis: a QM/MM study of chorismate mutase

Two different transition structures (TSs) have been located and characterized for the chorismate conversion to prephenate in Bacillus subtilis chorismate mutase by means of hybrid quantum-mechanical/molecular-mechanical (QM/MM) calculations. GRACE software, combined with an AM1/CHARMM24/TIP3P potential, has been used involving full gradient relaxation of the position of ca. 3300 atoms. These TSs have been connected with their respective reactants and products by the intrinsic reaction coordinate (IRC) procedure carried out in the presence of the protein environment, thus obtaining for the first time a realistic enzymatic reaction path for this reaction. Similar QM/MM computational schemes h…

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 n…

A Quantum Mechanic/Molecular Mechanic Study of the Wild-Type and N155S Mutant HIV-1 Integrase Complexed with Diketo Acid

Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. Recently, mutation studies have been reported that have shown that a certain degree of viral resistance to diketo acids (DKAs) appears when some amino acid residues of the IN active site are mutated. Mutations represent a fascinating experimental challenge, and we invite theoretical simulations for the disclosure of still unexplored features of enzyme reactions. The aim of this work is to understand the molecular mechanisms of HIV-1 IN drug resistance, which will be useful for designing anti-HIV inhibitors with unique resistance profiles. In this study, we use mo…

Vibrational Dynamics of Histamine Monocation in Solution: An Experimental (FT-IR, FT-Raman) and Theoretical (SCRF-DFT) Study

spectra of histamine monocation in solution, based on the isotopic shifts and a previous vibrational study in solid state. Force field and normal coordinate calculations were computed to support these assignments. The ab initio force constants were transformed into a set of locally symmetrized internal coordinates and subsequently scaled to the experimental frequencies by using one specific and two generic scaling factors. The comparison in terms of vibrational frequencies and normal coordinate descriptions supported most of the proposed assignments. The theoretical infrared spectra for the two isotopomers on the basis of the ab initio intensities also showed a good correlation with the exp…

Comparative computational analysis of different active site conformations and substrates in a chalcone isomerase catalyzed reaction.

Chalcone isomerase catalyzes the transformation of chalcones to flavanones. We present a computational study of the rate-limiting chemical step, an intramolecular Michael addition of a 2'-oxyanion to the alpha,beta-double bound. By using quantum mechanical/molecular mechanical hybrid methods we traced the free-energy profiles associated with the reaction of two different substrates (chalcone and 6'-deoxychalcone) in two different conformations of the active site that are described in the different crystallographic structures available. We have obtained significant differences (about 4 kcal/mol) in the free-energy barriers calculated for the two active sites. According to our results, the ac…

Intramolecular proton transfer of serine in aqueous solution. Mechanism and energetics

Serine amino acid in aqueous solution is theoretically studied at the B3PW91/6-31+G** level using a dielectric continuum solvent model. Neutral and zwitterionic structures in the gas phase and in solution are described and the proton-transfer mechanism is discussed. A neutral conformation in which the carboxyl hydrogen atom is already oriented toward the amino group seems to be the absolute energy minimum in the gas phase and the most stable neutral form in solution. The absolute energy minimum in solution is a zwitterionic form. The energy barrier for proton transfer is predicted to be very small, in particular when zero-point-energy contributions are added. Our calculations allow the dyna…

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.

FT-Raman and QM/MM study of the interaction between histamine and DNA

The interaction between histamine and highly polymerized calf-thymus DNA has been investigated using FT-Raman spectroscopy and the hybrid QM/MM (quantum mechanics/molecular mechanics) methodology. Raman spectra of solutions containing histamine and calf-thymus DNA, at different molar ratios, were recorded. Solutions were prepared at physiological settings of pH and ionic strength, using both natural and heavy water as the solvent. The analysis of the spectral changes on the DNA Raman spectra when adding different concentrations of histamine allowed us to identify the reactive sites of DNA and histamine, which were used to built two minor groove and one intercalated binding models. They were…

An ab initio study of the unimolecular decomposition mechanism of formamidine. 4-31G Characterization of potential energy hypersurface

Ab initio MO calculations have been carried out for the unimolecular decomposition of formamidine. The Hartree–Fock method in LCAO approximation with the 4-31G basis set was used. The 4-31G potential hypersurface has been further studied. The stationary points (R, TS, and P) were localized. A reaction analysis by correlation of bond-order indices and localized molecular orbitals demonstrated that the decomposition is an asynchronous process. The TS can be described as four-membered ring.

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 righ…

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.

Role of Protein Flexibility in Enzymatic Catalysis:  Quantum Mechanical−Molecular Mechanical Study of the Deacylation Reaction in Class A β-Lactamases

We present a theoretical study of a mechanism for the hydrolysis of the acyl-enzyme complex formed by a class A beta-lactamase (TEM1) and an antibiotic (penicillanate), as a part of the process of antibiotic's inactivation by this type of enzymes. In the presented mechanism the carboxylate group of a particular residue (Glu166) activates a water molecule, accepting one of its protons, and afterward transfers this proton directly to the acylated serine residue (Ser70). In our study we employed a quantum mechanics (AM1)-molecular mechanics partition scheme (QM/MM) where all the atoms of the system were allowed to relax. For this purpose we used the GRACE procedure in which part of the system …

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 funct…

Theoretical rotational constants of MeCnN species

Abstract By means of SCF HF “ab initio” calculations with STO-3G and 6-31G basis sets, the geometric parameters of methylcyanopolyynes (MeCnN n=3, 5, 7 and 9) have been obtained. B0=0.3748 GHz for MeC7N and B0=0.2708 GHz for MeC9N, with a STO-3G basis set, were obtained. Both species, unstable in the laboratory, are still undetected in the interstellar medium, although their existence is very probable.

Structural and vibrational study of the tautomerism of histamine free-base in solution.

Infrared and Raman spectroscopy in H(2)O and D(2)O and quantum Density Functional calculations were used to determine the structure of histamine free-base in aqueous solution. A quantum mechanical study of the tautomeric equilibrium of histamine free-base in solution was performed at the 6-311G level. Electronic correlation energies were included by using the hybrid functional B3LYP. The solvent was simulated as a continuum characterized by a dielectric constant, and the quantum system (solute) was placed in an ellipsoidal cavity. Solute-solvent electrostatic interaction was calculated by means a multipolar moment expansion introduced in the Hamiltonian. Four relevant histamine conformation…

Computer-Aided Rational Design of Catalytic Antibodies: The 1F7 Case.