Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations

Yaron Pshetitsky, Reuven Eitan, Gilit Verner, Amnon Kohen, Dan Thomas Major

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)5179-5189
Number of pages11
JournalJournal of Chemical Theory and Computation
Issue number10
StatePublished - 11 Oct 2016

Bibliographical note

Funding Information:
This work has been supported by the Israel Science Foundation (Grant no. 2146/15) and the United States-Israel Binational Science Foundation (Grant no. 2012340).

Publisher Copyright:
© 2016 American Chemical Society.


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