Mechanistic aspects of biological redox reactions involving NADH 1: Ab initio quantum chemical structures of the 1-methyl-nicotinamide and 1-methyl-dihydronicotinamide coenzyme analogues

Cummins, Peter L.; Gready, Jill E.

doi:10.1016/0166-1280(89)80032-6

Cited by 18 publications

(18 citation statements)

References 18 publications

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“…However, the PM3 geometry and activation enthalpy for hydride transfer in this system agree reasonably well with ab initio values for related hydride transfers (Wu & Houk, 1991Wu et al, 1995). Furthermore, in contrast to proton-transfer transition states, which are poorly represented by semiempirical methods (Zheng et al, 1993;Rı ´os & Rodrı ´guez, 1992), hydride transfers are fairly well-represented (Cummins & Gready, 1989Zheng et al, 1993;Andre ´s et al, 1995). Nonetheless, ab initio calculations of reduction of NAD + by zinc-bound aldehyde hydrate seem warranted.…”

Section: Discussionsupporting

confidence: 66%

Mechanism of Aldehyde Oxidation Catalyzed by Horse Liver Alcohol Dehydrogenase

et al. 1996

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The mechanism of oxidation of benzaldehyde to benzoic acid catalyzed by horse liver alcohol dehydrogenase (HLADH) has been investigated using the HLADH structure at 2.1 A resolution with NAD+ and pentafluorobenzyl alcohol in the active site [Ramaswamy et al. (1994) Biochemistry 33,5230-5237]. Constructs for molecular dynamics (MD) investigations with HLADH were obtained by a best-fit superimposition of benzaldehyde or its hydrate on the pentafluorobenzyl alcohol bound to the active site Zn(II)ion. Equilibrium bond lengths, angles, and dihedral parameters for Zn(II) bonding residues His67, Cys46, and Cys174 were obtained from small-molecule X-ray crystal structures and an ab initio-derived parameterization of zinc in HLADH [Ryde, U. (1995) Proteins: Struct., Funct., Genet. 21,40-56]. Dynamic simulations in CHARMM were carried out on the following three constructs to 100 ps: (MD1) enzyme with NAD+, benzaldehyde, and zinc-ligated HO-in the active site; (MD2) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-R oxygen, with a proton residing on the pro-S oxygen; and (MD3) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-S oxygen, with a proton residing on the pro-R oxygen. Analyses were done of 800 sample conformations taken in the last 40 ps of dynamics. Structures from MD1 and MD3 were used to define the initial spatial arrangements of reactive functionalities for semiempirical PM3 calculations. Using PM3, model systems were calculated of ground states and some transition states for aldehyde hydration, hydride transfer, and subsequent proton shuttling. With benzaldehyde and zinc-bound hydroxide ion in the active site, the oxygen of Zn(II)-OH resided at a distance of 2.8-5.5 A from the aldehyde carbonyl carbon during the dynamics simulation. This may be compared to the PM3 transition state for attack of the Zn(II)-OH oxygen on the benzaldehyde carbonyl carbon, which has an O...C distance of 1.877 A. HLADH catalysis of the aldehyde hydration would require very little motion aside from that in the ground state. Two simulations of benzaldehyde hydrate ligated to zinc (MD2 and MD3) both showed close approach of the aldehyde hydrate hydrogen to NAD+C4, varying from 2.3 to 3.3 A, seemingly favorable for the hydride transfer reaction. The MD2 configuration does not allow proton shuttling. On the other hand, when the pro-S oxygen is ligated to zinc (MD3), the proton on the pro-R oxygen averages 2.09 A from the hydroxyl oxygen of Ser48 such that initiation of shuttling of protons via Ser48 to the ribose 2'-hydroxyl oxygen to the 3'-hydroxyl oxygen to His51 nitrogen is sterically favorable. PM3 calculations suggest that this proton shuttle represents a stepwise reaction which occurs subsequent to hydride transfer. The PM3 transition state for hydride transfer based on the MD3 configuration has the transferring hydride 1.476 A from C4 of NAD+ and 1.433 A from the aldehyde alpha-carbon.

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Section: Discussionsupporting

confidence: 66%

Mechanism of Aldehyde Oxidation Catalyzed by Horse Liver Alcohol Dehydrogenase

et al. 1996

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“…Although the AM1 model underestimates the increase in energy for out of plane rotation of the side chain, we would not expect such a rotation to be prohibited at a higher level of QM theory. 49 While the H bonds between nicotinamide and DHFR fix the ring in the general position that is necessary for hydride-ion transfer, rotation about the C5᎐C7 bond may allow some additional flexibility for improving the relative orientation of the substrate and nicotinamide. This configuration is very different from gas-phase analogue reactions in which the side chain may be involved in H-bonded complex formation between reacting fragments.…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics and free energy perturbation study of hydride-ion transfer step in dihydrofolate reductase using combined quantum and molecular mechanical model

Cummins

Gready

1998

J. Comput. Chem.

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“…Thus, as the transition state is approached, the nicotinamide pyridine ring would twist slightly relative to its carboxamide group. Such a rotation seems feasible since the planar trans conformation of 1 -methyldihydronicotinamide and conformations in which the carboxamide group is rotated up to 30°f rom this conformation have approximately equal energies (Cummins & Gready, 1989). However, the same is unlikely to be true for thioNADPH.…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of chicken liver dihydrofolate reductase: Binary thioNADP+ and ternary thioNADP+.cntdot.biopterin complexes

McTigue¹,

Davies²,

Kaufman³

et al. 1993

Biochemistry

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The role of the 3'-carboxamide substituent of NADPH in the reduction of pteridine substrates as catalyzed by dihydrofolate reductase (EC 1.5.1.3, DHFR) has been investigated by determining crystal structures at 2.3 A of chicken liver DHFR in a binary complex with oxidized thionicotinamide adenine dinucleotide (thioNADP+) and in a ternary complex with thioNADP+ and biopterin. These structures are isomorphous with those previously reported for chicken liver DHFR [Volz, K.W., Matthews, D.A., Alden, R.A., Freer, S. T., Hansch, C., Kaufman, B. T., & Kraut, J. (1982) J. Biol. Chem. 257, 2528-2536]. ThioNADPH, which has a 3'-carbothioamide substituent in place of a 3'-carboxamide, functions very poorly as a coenzyme for DHFR [Williams, T. J., Lee, T. K., & Dunlap, R. B. (1977) Arch, Biochem. Biophys. 181, 569-579; Stone, S. R., Mark, A., & Morrison, J. F. (1984) Biochemistry 23, 4340-4346]. Comparisons show that, while NADP+ and NADPH bind to DHFR with the pyridine ring and 3'-carboxamide coplanar, the thioamide group is twisted by 23 degrees from the pyridine plane in both the binary and ternary complexes. This twist appears to be due to steric conflict between the thioamide sulfur atom and both the pyridine ring at C4 and the adjacent protein backbone at Ala-9. It results in an unfavorably close contact between the sulfur and the biopterin pteridine ring (0.9 A less than the van der Waals separation) which, on the basis of the refined structure, greatly destabilizes the binding of biopterin.(ABSTRACT TRUNCATED AT 250 WORDS)

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Mechanistic aspects of biological redox reactions involving NADH 1: Ab initio quantum chemical structures of the 1-methyl-nicotinamide and 1-methyl-dihydronicotinamide coenzyme analogues

Cited by 18 publications

References 18 publications

Mechanism of Aldehyde Oxidation Catalyzed by Horse Liver Alcohol Dehydrogenase

Mechanism of Aldehyde Oxidation Catalyzed by Horse Liver Alcohol Dehydrogenase

Molecular dynamics and free energy perturbation study of hydride-ion transfer step in dihydrofolate reductase using combined quantum and molecular mechanical model

Crystal structures of chicken liver dihydrofolate reductase: Binary thioNADP+ and ternary thioNADP+.cntdot.biopterin complexes

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