ISSN:
0192-8651
Keywords:
Computational Chemistry and Molecular Modeling
;
Biochemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
,
Computer Science
Notes:
As part of a study of factors controlling biological redox reactions of nicotinamide cofactors [nicotinamide adenine dinucleotide (phosphate) NAD(P)H], we have investigated the effect on a model reaction of the conformational state (cis or trans) of the carboxamide side chain, using quantum chemical methods. The reaction is that for the enzyme dihydrofolate reductase between the NADPH analogue, 1-methyl-dihydronicotinamide, and the protonated forms of the folate and dihydrofolate substrate analogues, pyrazine and dihydropyrazine. Some calculations on pterin and dihydropterin substrate analogues were also carried out in order to gauge the effects of inter-ring coupling. The influence of carboxamide side-chain conformation of nicotinamide on the energetics of the hydride-ion transfer, and on the structures of the transition states and stable intermolecular-interaction complexes, are examined as a function of the orientation of approach of the reactants. These approach geometries include those corresponding to the observed binding of cofactor and either substrate or inhibitor in the enzyme active site. Reactant, product, reactants-complex, and transition-state geometries were optimized at the semiempirical AM1 level, while ab initio SCF/STO-3G and SCF/3-21G single-point calculations were carried out at the AM1 optimized geometries for all species, as well as full geometry optimizations for isolated reactants and products. The results show that reactants-complex and transition-state energies are lower for the trans conformer of dihydronicotinamide than for the cis conformer, due to more favorable H-bonding or electrostatic interactions with the protonated substrate. Also, consideration of the structural parameters, including reaction coordinate bond lengths, ring geometries, and charge distributions, indicate that the trans transition states are more product-like than those for the cis. For the (trans) approaches corresponding to the enzymic orientation for substrate, the intermolecular interaction for the folate reaction lacks the stabilizing influence of the formal H-bond which is present for the dihydrofolate reaction, and consequently the reactants-complex and transition state are less stable.
Additional Material:
8 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcc.540110703
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