Molecular dynamics and free energy perturbation study of hydride-ion transfer step in dihydrofolate reductase using combined quantum and molecular mechanical model
✍ Scribed by Peter L. Cummins; Jill E. Gready
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 228 KB
- Volume
- 19
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
We used molecular dynamics simulation and free energy Ž . perturbation FEP methods to investigate the hydride-ion transfer step in the Ž . mechanism for the nicotinamide adenine dinucleotide phosphate NADPHdependent reduction of a novel substrate by the enzyme dihydrofolate reductase Ž . DHFR . The system is represented by a coupled quantum mechanical and Ž . molecular mechanical QMrMM 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 Ž . QM and MM regions with the addition of ''link'' atoms F, CH , and H .
3
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 QMrMM model. The hydride-ion transfer was also carried out over several FEP pathways, and the QM and QMrMM component free energies thus calculated were found to be state Ž . functions i.e., independent of pathway . A ca. 10 kcalrmol increase in free energy for the hydride-ion transfer with an activation barrier of ca. 30 kcalrmol was calculated. The increase in free energy on the hydride-ion transfer arose largely from the QMrMM component. Analysis of the QMrMM energy components suggests that, although a number of charged residues may contribute to the free energy change through long-range electrostatic interactions,