Molecular Dynamics Simulations Can Reproduce the Subtle Differences in NADP and NHDP Binding to Isocitrate Dehydrogenase

Mireia Garcia-Viloca, Peter A. Kollman

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)


Koshland and co-workers have shown, using X-ray crystallography and enzymology, that one can rationalize the significantly slower rate of catalysis with the cofactor NHDP than with NADP (NHDP is an NADP analog with the adenine replaced by hypoxanthine) of isocitrate dehydrogenase (IDH) acting on isocitrate. The crystal structures of these cofactors bound to the enzyme show that the mutation of adenine to hypoxanthine, albeit quite distant from the site of the reaction, the nicotinamide ring being on the other side of the cofactor, causes the substrate and cofactor to be less optimally aligned for catalysis. We show that the difference in the isocitrate substrate-nicotinamide interactions observed crystallographically can be successfully simulated using molecular dynamics methods. Whereas the simulation starting from the observed NADP-isocitrate-IDH structure retains the favorable distance and orientation for hydride attack found crystallographically, the simulation starting with the same geometry but substituting NHDP for NADP, which involves a change in hydrogen-bonding approximately 10 Å from the nicotinamide and citrate moieties, leads to a distance for the nicotinamide-isocitrate interaction similar to that observed in the NHDP-IDH-isocitrate crystal structure. Control simulations on NHDP-IDH-citrate, starting with the observed crystallographic complex, maintain the longer nicotinamide citrate distance found experimentally. © 1999 John Wiley & Sons, Inc.
Original languageEnglish
Pages (from-to)231-243
JournalInternational Journal of Quantum Chemistry
Issue number3
Publication statusPublished - 1 Jan 1999


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