title: Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations.
abstract: The coenzyme nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) play ubiquitous roles as oxidizing and reducing agents in nature. The binding, and possibly the chemical redox step, of NAD+/NADH may be influenced by the cofactor conformational distribution and, in particular, by the ribose puckering of its nicotinamide-ribonucleoside (NR) moiety. In many hybrid quantum mechanics-molecular mechanics (QM/MM) studies of NAD+/NADH dependent enzymes, the QM region is treated by semiempirical (SE) methods. Recent work suggests that SE methods do not adequately describe the ring puckering in sugar molecules. In the present work we adopt an efficient and practical strategy to correct for this deficiency for NAD+/NADH. We have implemented a cost-effective correction to a SE Hamiltonian by adding a correction potential, which is defined as the difference between an accurate benchmark density functional theory (DFT) potential energy surface (PES) and the SE PES. In practice, this is implemented via a B-spline interpolation scheme for the grid-based potential energy difference surface. We find that the puckering population distributions obtained from free energy QM(SE)/MM simulations are in good agreement with DFT and in fair accord with experimental results. The corrected PES should facilitate a more accurate description of the ribose puckering in the NAD+/NADH cofactor in simulations of biological systems.
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Pshetitsky
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Eitan
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Gilit
authors.initials: G
authors.lastname: Verner
authors.affiliation: Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Amnon
authors.initials: A
authors.lastname: Kohen
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Dan Thomas
authors.initials: DT
authors.lastname: Major
mesh_terms: D002241:Carbohydrates / Q000737:chemistry; D005740:Gases / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009243:NAD / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory; D014867:Water / Q000737:chemistry
chemical_list: D002241:Carbohydrates; D005740:Gases; D014867:Water; D009243:NAD