Theoretical Modeling on the Reaction Mechanism of p-Nitrophenylmethylphosphate Alkaline Hydrolysis and its Kinetic Isotope Effects
We have studied the alkaline hydrolysis of p-nitrophenylmethylphosphate (p-NPmP) in aqueous solution by means of polarizable continuum models and by hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods. The theoretical predictions of kinetic isotope effects (KIEs) are in very good agreement with the experimental data, confirming a concerted asynchronous molecular mechanism. In addition, comparison of high level DFT theory with semiempirical AM1/d Hamiltonian has allowed checking the reliability of the later to be used in modeling very large molecular models containing phosphorus atoms.
Linking Electrostatic Effects and Protein Motions in Enzymatic Catalysis. A Theoretical Analysis of Catechol O-Methyltransferase
The role of protein motions in enzymatic catalysis is the subject of a hot scientific debate. We here propose the use of an explicit solvent coordinate to analyze the impact of environmental motions during the reaction process. The example analyzed here is the reaction catalyzed by catechol O-methyltransferase, a methyl transfer reaction from S-adenosylmethionine (SAM) to the nucleophilic oxygen atom of catecholate. This reaction proceeds from a charged reactant to a neutral product, and then a large electrostatic coupling with the environment could be expected. By means of a two-dimensional free energy surface, we show that a large fraction of the environmental motions needed to attain the…
Hybrid Schemes Based on Quantum Mechanics/Molecular Mechanics Simulations
The development of characterization techniques, advanced synthesis methods, as well as molecular modeling has transformed the study of systems in a well-established research field. The current research challenges in biocatalysis and biotransformation evolve around enzyme discovery, design, and optimization. How can we find or create enzymes that catalyze important synthetic reactions, even reactions that may not exist in nature? What is the source of enzyme catalytic power? To answer these and other related questions, the standard strategies have evolved from trial-and-error methodologies based on chemical knowledge, accumulated experience, and common sense into a clearly multidisciplinary …
Analysis of the Decarboxylation Step in Mammalian Histidine Decarboxylase
We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct (external aldimine) in the active site of rat histidine decarboxylase. By means of molecular dynamics simulations, we traced the potential of mean force corresponding to the decarboxylation reaction of the adduct both in the active site of the enzyme and in aqueous solution. By comparing this process in both media, we have identified the key electrostatic interactions that explain the lowering of the free energy barrier in the enzyme. Our analysis also offers a va…