ISSN:
0192-8651
Keywords:
quantum mechanical/molecular mechanical
;
free energy
;
hydride ion
;
molecular dynamics
;
catalysis
;
Chemistry
;
Theoretical, Physical and Computational Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
,
Computer Science
Notes:
We used molecular dynamics simulation and free energy perturbation (FEP) methods to investigate the hydride-ion transfer step in the mechanism for the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a novel substrate by the enzyme dihydrofolate reductase (DHFR). The system is represented by a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1 semiempirical molecular orbital method for the reacting substrate and NADPH cofactor fragments, the AMBER force field for DHFR, and the TIP3P model for solvent water. The FEP calculations were performed for a number of choices for the QM system. The substrate, 8-methylpterin, was treated quantum mechanically in all the calculations, while the larger cofactor molecule was partitioned into various QM and MM regions with the addition of “link” atoms (F, CH3, and H). Calculations were also carried out with the entire NADPH molecule treated by QM. The free energies of reaction and the net charges on the NADPH fragments were used to determine the most appropriate QM/MM model. The hydride-ion transfer was also carried out over several FEP pathways, and the QM and QM/MM component free energies thus calculated were found to be state functions (i.e., independent of pathway). A ca. 10 kcal/mol increase in free energy for the hydride-ion transfer with an activation barrier of ca. 30 kcal/mol was calculated. The increase in free energy on the hydride-ion transfer arose largely from the QM/MM component. Analysis of the QM/MM energy components suggests that, although a number of charged residues may contribute to the free energy change through long-range electrostatic interactions, the only interaction that can account for the 10 kcal/mol increase in free energy is the hydrogen bond between the carboxylate side chain of Glu30 (avian DHFR) and the activated (protonated) substrate. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 977-988, 1998
Additional Material:
4 Ill.
Type of Medium:
Electronic Resource
