Computational study on hydrolysis of cefotaxime in gas phase and in aqueous solution

We are presenting a theoretical study of the hydrolysis of a β‐lactam antibiotic in gas phase and in aqueous solution by means of hybrid quantum mechanics/molecular mechanics potentials. After exploring the potential energy surfaces at semiempirical and density functional theory (DFT) level, potentials of mean force have been computed for the reaction in solution with hybrid PM3/TIP3P calculations and corrections with the B3LYP and M06‐2X functionals. Inclusion of the full molecule of the antibiotic, Cefotaxime, in the gas phase molecular model has been demonstrated to be crucial since its carboxylate group can activate a nucleophilic water molecule. Moreover, the flexibility of the substrate implies the existence of a huge number of possible conformers, some of them implying formation of intramolecular hydrogen bond interaction that can determine the energetics of the conformers defining the different states along the reaction profile. The results show PM3 provides results that are in qualitative agreement with DFT calculations. The free energy profiles show a step‐wise mechanism that is kinetically determined by the nucleophilic attack of a water molecule activated by the proton transfer to the carboxylate group of the substrate (the first step). However, since the main role of the β‐lactamase would be reducing the free energy barrier of the first step, and keeping in mind the barrier obtained from second intermediate to products, population of this second intermediate could be significant and consequently experimentally detected in β‐lactamases, as shown in the literature. © 2012 Wiley Periodicals, Inc.