The mechanism of formamide hydrolysis in water from ab initio calculations and simulations.

The neutral hydrolysis of formamide in water is a suitable reference to quantify the efficiency of proteolytic enzymes. However, experimental data for this reaction has only very recently been obtained and the kinetic constant determined experimentally is significantly higher than that predicted by previous theoretical estimations. In this work, we have investigated in detail the possible mechanisms of this reaction. Several solvent models have been considered that represent a considerable improvement on those used in previous studies. Density functional and ab initio calculations have been carried out on a system which explicitly includes the first solvation shell of the formamide molecule…

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…

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

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…

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…

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. II. Charge separation processes

A new approach to carry out molecular dynamics simulations of chemical reactions in solution using combined density functional theory/molecular mechanics potentials is presented. We focus our attention on the analysis of reactive trajectories, dynamic solvent effects and transmission coefficient rather than on the evaluation of free energy which is another important topic that will be examined elsewhere. In a previous paper we have described the generalities of this hybrid molecular dynamics method and it has been employed to investigate low energy barrier proton transfer process in water. The study of processes with activation energies larger than a few kT requires the use of specific tech…

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. I. Proton transfer in strongly H-bonded complexes

The first molecular dynamics (MD) simulation of a chemical process in solution with an ab initio description of the reactant species and a classical representation of the solvent is presented. We study the dynamics of proton (deuterium) transfer in strongly hydrogen-bonded systems characterized by an energy surface presenting a double well separated by a low activation barrier. We have chosen the hydroxyl-water complex in liquid water to analyze the coupling between the reactive system and the environment. The proton is transferred from one well to the other with a frequency close to 1 ps−1 which is comparable to the low-frequency band associated to hindered translations, diffusional transl…