Dan Thomas Major

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Combined quantum mechanical/molecular mechanical simulations have been carried out to investigate the origin of the carbon acidity enhancement in the alanine racemization reaction catalyzed by alanine racemase (AlaR). The present study shows that the enhancement of carbon acidity of alpha-amino acids by the cofactor pyridoxal 5'-phosphate (PLP) with an(More)
We report computational results of efficient catalysis of depro-tonation of L-alanine, by pyridoxal 5′-phosphate (PLP) and by alanine racemase (AlaR), which is the result of large solvation effects of the external aldimine cofactor to lower the pK a of the R-amino acid by 13 units and transition state stabilization (14.1 kcal/mol) by the enzyme. AlaR(More)
We have carried out a mixed molecular dynamics and centroid path integral simulation using a combined quantum mechanical and molecular mechanical (QM/MM) potential to study the anomalous Brønsted relationship between rates and equilibria for deprotonation of nitroalkanes in water, which is known as the nitroalkane anomaly. The deprotonation process is(More)
A bisection sampling method was implemented in path integral simulations of chemical reactions in solution in the framework of the quantized classical path approach. In the present study, we employ a combined quantum mechanical and molecular mechanical (QM/MM) potential to describe the potential energy surface and the path integral method to incorporate(More)
A bisection sampling method is implemented in the framework of a quantized classical path algorithm to include nuclear quantum effects in path integral simulations. The present study examines the convergence of these calculations on two model systems with respect to the number of beads used in the polymer chain and the number of configurations both in(More)
In this review we give an overview of the field of Computational enzymology. We start by describing the birth of the field, with emphasis on the work of the 2013 chemistry Nobel Laureates. We then present key features of the state-of-the-art in the field, showing what theory, accompanied by experiments, has taught us so far about enzymes. We also briefly(More)
The rate expression of traditional transition state theory (TST) assumes no recrossing of the transition state (TS) and thermal quasi-equilibrium between the ground state and the TS. Currently, it is not well understood to what extent these assumptions influence the nature of the activated complex obtained in traditional TST-based simulations of processes(More)
An integrated Feynman path integral-free energy perturbation and umbrella sampling (PI-FEP/UM) method has been used to investigate the kinetic isotope effects (KIEs) in the proton transfer reaction between nitroethane and acetate ion in water. In the present study, both nuclear and electronic quantum effects are explicitly treated for the reacting system.(More)
An integrated centroid path integral and free-energy perturbation-umbrella sampling (PI-FEP/UM) method for computing kinetic isotope effects (KIEs) for chemical reactions in solution and in enzymes is presented. The method is based on the bisection sampling in centroid path integral simulations to include nuclear quantum effects to the classical potential(More)