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.

Palladium‐Catalyzed/Norbornene‐Mediated CH Activation/ N‐Tosylhydrazone Insertion Reaction: A Route to Highly Functionalized Vinylarenes

“…[55,56] The puckering of the ribose unit wasd efined by following the triangular decomposition strategy. [57,58] The reference plane is determined by the atoms O4',C 2 ',a nd C3'.T he puckering is then described by using two angles:t hose angles formed by the reference plane with the planes O4',C 4 ',a nd C3' (angle f 1 ) and O4',C 1 ',a nd C2' (angle f 2 ). In fact, an equivalent definition would be to use the dihedral angles C2'-C3'-O4'-C4' (f 1 ) and C3'-C2'-O4'-C1' (f 2 ).…”

Phosphoryl‐Transfer Reaction in RNA under Alkaline Conditions

“…The puckering of the ribose unit was defined by following the triangular decomposition strategy . The reference plane is determined by the atoms O4′, C2′, and C3′.…”

A Multidimensional B-Spline Correction for Accurate Modeling Sugar Puckering in QM/MM Simulations

“…4–8 Considerable effort has been devoted to the study of sugar ring conformation energy profiles with molecular simulations and quantum mechanical methods, including approximate density-functional and semiempirical models. 9–14 Torsion angle rotational barriers are particularly problematic for semiempirical methods based on the neglect of diatomic differential overlap (NDDO) approximation. 14–17 Very recently, we performed a computational study of sugar pucker potential energy surfaces, and we introduced a nonelectronic correction to semiempirical models to improve their quality with respect to MP2 results.…”

“…9–14 Torsion angle rotational barriers are particularly problematic for semiempirical methods based on the neglect of diatomic differential overlap (NDDO) approximation. 14–17 Very recently, we performed a computational study of sugar pucker potential energy surfaces, and we introduced a nonelectronic correction to semiempirical models to improve their quality with respect to MP2 results. 16 Sugar pucker corrections were implemented using a multidimensional B-spline correction method 16 (BMAP correction) for coupling the torsion angle energy terms.…”

“…18–22 The BMAP correction strategy has been adopted by others, who have successfully extended it to improve sugar pucker profiles in the nicotinamide ribonucleoside. 14 Recent orthogonalization-corrected semi-empirical methods also have the potential to provide good treatment to sugar ring conformations. 23 …”