Dan Thomas Major

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Most enzymatic reactions have very large and remarkably similar apparent second-order rate constants, kcat/KM, at mean values of about 107 M-1 s-1 with kcat in the range of 101000 s-1.1-3 In fact, many reactions approach the diffusional encounter rate at the limited enzyme concentration (<10-5 M) in the cell.4 Wolfenden illustrated the catalytic power of(More)
In the companion paper, part 1, we described the construction of an improved molecular model for the h-P2Y1 receptor (h-P2Y1-R) and proposed a rational for the stereoelectronic selectivity of the receptor. Here, we extend our studies on the molecular recognition of the h-P2Y1-R to the exploration of the diastereoselectivity of this receptor. For this(More)
P2Y receptors (P2Y-Rs) are attractive pharmaceutical targets due to their involvement in the modulation of many tissues and organs. The lack of experimental structural data on P2Y-Rs impedes structure-based drug design. The need to elucidate the receptor's molecular recognition, together with the limitations of previous receptor models, triggered the(More)
A practical approach to treat nuclear quantum mechanical (QM) effects in simulations of condensed phases, such as enzymes, is via Feynman path integral (PI) formulations. Typically, the standard primitive approximation (PA) is employed in enzymatic PI simulations. Nonetheless, these PI simulations are computationally demanding due to the large number of(More)
The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl phosphate scaffold, are described. The physiological effects of the new compounds were evaluated in rat cardiac cell culture regarding Ca(2+) elevation and contractility. The results indicate biochemical and physiological profiles similar to those of ATP, although at higher(More)
A method for preparation of nanoparticles of poorly water-soluble organic materials is presented. By this method, an oil-in-water microemulsion containing a volatile solvent with dissolved model material, propylparaben, undergoes solvent evaporation and conversion into nanoparticles by spray drying. The resulting powder can be easily dispersed in water to(More)
The origin of the catalytic proficiency of the cofactor-independent enzyme proline racemase (ProR) has been investigated by a combined classical and quantum simulation approach with a hybrid quantum mechanics/molecular mechanics potential energy surface. The present study shows that the ProR reaction mechanism is asynchronous concerted with no distinct(More)
Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of more than 60,000 known natural products. This abundance of compounds is generated using a very limited pool of substrates based on linear isoprenoids. The astounding chemodiversity obtained by terpene cyclases suggests a tremendous catalytic challenge to these(More)
Orotidine 5'-monophosphate (OMP) decarboxylase (ODCase) catalyzes the decarboxylation of OMP to uridine 5'-monophosphate (UMP). Numerous studies of this reaction have suggested a plethora of mechanisms including covalent addition, ylide or carbene formation, and concerted or stepwise protonation. Recent experiments and simulations present strong evidence(More)
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)