As a test for the applicability of the density functional theory
to the system containing intramolecular hydrogen
bonds, calculations were performed on propen-1,2,3-triol, the feasible
intermediate in the epimerization of
dihydroxyacetone and glyceraldehyde enantiomers. A comparison is
made between results obtained by Becke's
three parameter hybrid functional (for exchange) with gradient
corrections provided by the LYP correlation
functional (B3LYP) and those predicted at the ab initio
Møller−Plesset second-order (MP2) level. The
calculated minimum energy structures are in excellent agreement with
respect to both energy and geometries
of hydrogen-bonded structures. Earlier and recent studies suggest
that, generally, the nonlocal B3LYP
approximation leads to a very accurate overall description of
intramolecular hydrogen-bonded systems. We
propose a new, more efficient computational protocol, which may be
useful in the study of the biologically
important molecules at a level of accuracy usually only provided by
traditional post-Hartree−Fock ab initio
methods.
Among the conformers of the title compounds, all stable
structures found reveal hydrogen bonding to an
sp2
oxygen atom in five- or six-membered rings and usually cooperative
effects. Nonlocal density functional
calculations using different functionals prove the applicability of DFT
to study geometries of systems containing
intramolecular hydrogen bonds. The hydrogen bond parameters
obtained applying the B3LYP approximation
exhibit perfect agreement with those calculated at the MP2 level.
The local gradient correction does not
provide encouraging results.
Background: Molecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol ( Figure 1) both in solution and at the β-tubulin protein binding site.
The conformational properties of epothilone A have been analyzed in detail using electronic structure calculations to better understand the effect of intramolecular hydrogen bonding on the conformational energies of this highly potent anticancer molecule. Single-point second-order Møller-Plesset calculations done in vacuo at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level yielded data on the relative stability of conformers that were more distinct than data obtained from the standard DFT model, although the structural trends are in fair agreement. We studied torsional profiles of both hydroxyl groups and sampled energies of the side chain and thiazole moiety rotamers within the whole set of all experimentally accessible conformers. The aldol hydrogen bonds, though relatively weak, generally contribute to the conformational profile, while dipole-dipole interactions, ester group puckering, transannular repulsions between hydrogen atoms, steric effects, and syn-pentane effects have a limited influence. A salient result of our calculations is the determination that the energy of the clustered exo conformer P01 lays 9.3 kcal/mol below that of the extended, experimental conformer P11, apparently due to the unconstrained, near linear 3-OH hydrogen bond to thiazole. Another finding to be noted is the corroboration of the remarkable ability of 3-OH to form transannular hydrogen bonding with the epoxide, which releases the conformational strain of the macroring and thus leads to extra stabilization energy within the endoW subset. Finally, we found that the general trend of the conformer populations of epothilone A obtained from conformational energies resembles those derived from experiments and can be used to interpret values of NMR vicinal coupling constants. The calculated geometries and energies provide essential data for further discussion of the mechanism of biological activity of epothilone A and might be of importance in the explanation of its ADME properties.
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