Ab initio rotational constants of interstellar species: Cyanoacetylene hydrogenated derivatives

By means of ab initio calculations, the rotational constants and dipole moments of H_nC₃N (n = 1, 3, 5, 7, and 9) species have been calculated at the HF / 6-31G * level of theory. Selected cases have been also calculated at the MP 2/6-31G * level and the influence of calculation level on rotational constant values is briefly discussed. Some of these species were discovered in the interstellar medium, while others have still not been detected there, although their existence is very probable. The results given here could help in their detection. © 1993 John Wiley & Sons, Inc.     

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 presenting a structure similar to the transition state of the reaction to be catalyzed--with shorter distances between the carbon atoms to be bonded and more diaxial character. With respect to the reorganization effect, an energy decomposition analysis of the potential energies of the reactive reactant and of the reaction transition state in aqueous solution and in the enzyme shows that the enzyme structure is better adapted to the transition structure. This means not only a more negative electrostatic interaction energy with the transition state but also a low enzyme deformation contribution to the energy barrier. Our calculations reveal that the structure of the enzyme is responsible for stabilizing the transition state structure of the reaction, with concomitant selection of the reactive form of the reactants. This is, the same enzymatic pattern that stabilizes the transition structure also promotes those reactant structures closer to the transition structure (i.e., the reactive reactants). In fact, both reorganization and preorganization effects have to be considered as the two faces of the same coin, having a common origin in the effect of the enzyme structure on the energy surface of the substrate.     

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, together with internal energy minimizations, has allowed free-energy profiles to be obtained for both CAs. The profiles show a smaller barrier for the matured form, which is in agreement with the experimental observation. Free-energy profiles were obtained with this methodology, thereby avoiding the much more demanding two-dimensional calculations of the energy surfaces that are normally required to study this kind of reaction. Structural analysis and energy evaluations of substrate-protein interactions have been performed from averaged structures, which allows understanding of how the single mutations carried out during the maturation process can be responsible for the observed fourfold enhancement of the catalytic rate constant. The conclusion is that the mutation effect in this studied germline CA produces a complex indirect effect through coupled movements of the backbone of the protein and the substrate.     

Stereoselectivity behavior of the AZ28 antibody catalyzed oxy-Cope rearrangement

Catalytic antibodies are very interesting not only because of the rate enhancement of the reactions that they catalyze but also because of the selectivities they can achieve that are sometimes not present in natural enzyme processes. We have selected the study of the stereoselectivity of the matured AZ28 that catalyzes an oxy-Cope rearrangement. For this particular case, the presence of a chiral center in the substrate provokes the existence of two different enantiomers, R and S. Furthermore, it is also possible to locate two different orientations for the hydroxyl group in the central ring of the substrate in the transition state, equatorial and axial, rendering two different conformers. In this paper we present the free energy profiles obtained for different substrate isomers in the cavity created by the matured catalytic antibody. Our simulations have reproduced the stereoselectivity of the matured AZ28, differentiating between the axial or equatorial orientations and preferentially stabilizing the S forms, at a qualitative level. Finally, the inclusion of the substrate-CA interactions in a flexible molecular model has allowed us to observe the different pattern of interactions that are related to different interaction energies, which seem to be crucial in the stereoselectivity behavior of the catalytic antibody.     

On the Merkulov Construction of A∞-(Co)Algebras

Ukrainian Mathematical Journal - The aim of this short note is to complete some aspects of a theorem proved by S. Merkulov in [Int. Math. Res. Not. IMRN, 3, 153–167 (1999)] (Theorem 3.4), as...     

Modeling β-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 solute's electronic properties. The discussion of results is focused on the role played by solute–solvent hydrogen bonds and solvent fluctuations on solute's structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1401–1411, 1999     

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 similar energy barriers at the rate-limiting step of the reaction path. In the first type, the β-lactam-water interaction takes place through the oxygen carbonyl atom and there is agreement between the maxima of the RDFs obtained here and the ab initio structure of the complexes previously reported. In the second type, the interaction takes place through the nitrogen atom and we do not predict a coordination layer around the β-lactam nitrogen atom. The results suggest that in aqueous solution hydrolysis of the carbonyl group is the most probable starting point for the overall hydrolysis reaction. Some discussion on the use of cluster models to represent the solvent effect is included. Received: 29 July 1998 / Accepted: 13 October 1998 / Published online: 1 February 1999