Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations in Gas Phase, Explicit Water and DHFR Enzyme Environments

The coenzyme nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH), and their phosphorylated counterparts NADPH/NADP+, participate in several redox hydride transfer reaction in nature¹. Several reports on enzymes containing NADH/NAD+ utilize the QM/MM hybrid method with the implementation of the low cost semiempirical (SE) methods to treat the QM region. The ribose sugar ring of NADH/NAD+ may influence the electronic configuration during the reaction, and therefore should be included in the QM region. Recent work^2-7 suggests that SE methods do not adequately describe the ring puckering in sugar molecules. In this work⁸ we corrected the SE Hamiltonian by adding a correction potential. This potential is the difference between an accurate DFT potential energy surface (PES) and the SE PES of the ribose sugar of NAD+/NADH obtained from the gas phase calculations. We found that the population distributions obtained from the free energy QM(corrected SE)/MM molecular dynamics simulations are in good agreement with DFT and experimental results. This modified Hamiltonian is further used to investigate the free energy profiles of NADH/NAD+ puckering in the enzymatic environment of Dihydrofolate Reductase (DHFR).

1. Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D., Molecular Biology of the Cell. 2 ed.; Garland Publishing: New York, 1989.
2. McNamara, J. P.; Muslim, A.-M.; Abdel-Aal, H.; Wang, H.; Mohr, M.; Hillier, I. H.; Bryce, R. A., Towards a quantum mechanical force field for carbohydrates: a reparametrized semi-empirical MO approach. Chem. Phys. Lett. 2004, 394 (4), 429-436.
3. Barnett, C. B.; Naidoo, K. J., Stereoelectronic and Solvation Effects Determine Hydroxymethyl Conformational Preferences in Monosaccharides. J. Phys. Chem. B 2008, 112 (48), 15450-15459.
4. Islam, S. M.; Roy, P.-N., Performance of the SCC-DFTB Model for Description of Five-Membered Ring Carbohydrate Conformations: Comparison to Force Fields, High-Level Electronic Structure Methods, and Experiment. J. Chem. Theory Comput. 2012, 8 (7), 2412-2423.
5. Govender, K.; Gao, J.; Naidoo, K. J., AM1/d-CB1: A Semiempirical Model for QM/MM Simulations of Chemical Glycobiology Systems. J Chem Theory Comput 2014, 10, 4694-4707.
6. Govender, K. K.; Naidoo, K. J., Evaluating AM1/d-CB1 for Chemical Glycobiology QM/MM Simulations. J. Chem. Theory Comput. 2014, 10 (10), 4708-4717.
7. Huang, M.; Giese, T. J.; Lee, T. S.; York, D. M., Improvement of DNA and RNA Sugar Pucker Profiles from Semiempirical Quantum Methods. J Chem Theory Comput 2014, 10 (4), 1538-1545.
8. Pshetitsky, Y.; Eitan, R.; Verner, G.; Kohen, A.; Major, D. T., Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations. J. Chem. Theory Comput. 2016.