Tautomeric Equilibria, II.
7-Aminopyrazolopyrimidine
Methodology
Molecular Mechanics (Force Field)
MNDO/AM1 PM3 (Semiempirical MO)
Techniques Used
Building, Optimization.
Analysis of Bonding Parameters. Output Analysis
Abstract. 7-Aminopyrazolopyrimidine (7-NH2-PP)
is present in a number of C-nucleosides with biological and pharmacological
properties. Its activity is related to an enzyme-bound structure where the
donor enzyme H-bonds at N3 and N7. It is not completely clear whether N7
or N8 is NH in the complex. Semiempirical MO theory will be used to estimate
the tautomeric preferences in this system as a means to probe the inherent
relative stabilities of the possible bound tautomers. Then, the effects
of protonation at various positions will be evaluated at the same level
of theory (not counting the presumably important influence of the enzyme!).
Note that the standard level of computation ignores solvent effects, although
some account of dielectric baths can be taken with more advanced methods.
Procedure. Build the N7-H and N8-H tautomers of
7-NH2-PP, preoptimize them with force field methods, and finish
with a full AM1 or PM3 optimization. Compare your energy difference between
tautomers to that computed at the ab initio level (see table below, results
quoted from M. Orozoco & F. Luque, J. Am. Chem. Soc., 117,
1378 (1995)).
Finally, compare the heats of formation for the N1 and N3 protonated
forms of the N7-H and N8-H tautomers. In principle, all these protonated
heats of formation may be compared to find the lowest overall energy. The
differences between the N7-H and N8-H tautomeric forms of the protonated
models are also given in the following table, from the same reference given
above.
Results.
| Tautomer |
DDH neutral |
DDH neutral N1-H+ |
DDH neutral N3-H+ |
| N7-H ( RHF 3-21G) |
+2.6 kcal/mol |
+7.8 kcal/mol |
+4.4 kcal/mol |
| N8-H ( RHF 3-21G) |
0.0 |
0.0 |
0.0 |
| N7-H (MP4 6-31G*) |
0.0 |
+8.1 |
+4.9 |
| N8-H (MP4 6-31G*) |
+ 0.9 |
0.0 |
0.0 |