228
A. B. Rozhenko
modeling the active site of HIV-1 IN were calculated. As objects for DFT calculations, the magnesium ions were surrounded with three formic acids and four water
molecules in order to mimic the IN binding site. In the optimized structures, the
most stable forms in water solution included deprotonated, enolized or phenolic
hydroxy groups, with the two eight-coordinated magnesium ions separated by a
distance 3.70–3.74 Å. Replacing one water in the complex with one molecule of
methanol mimiced the terminal 3′-OH of viral DNA, and the chelating complex
remained stable. Probably, after 3′-processing, in the binding site of IN the terminal
3′-OH of viral DNA interacts with one Mg
2 +
by chelation.
+
2
2
2
2+
+
+
2
2 +
2
1
1
+1
+
1
2
1
+1
2
)
&O
)
+
1
2
2+
2
2+
Wolschann et al. [103] used DFT calculations to identify the protonation state of
HIV-1 IN, in particular, residues Lys156 and Lys159, which are of importance for
binding 5CITEP inhibitor (88). The most favored conformations of 5CITEP were
derived at the B3LYP/6-31G(d,p) level of theory by a variation of two torsion angles, Tor1 (C19-C11-C9-C8) and Tor2 (N3-C5-C6-C8) (Fig. 7.8, left). The potential energy surface (PES) was analyzed at the HF/3-21G level with subsequent reoptimization of the structures corresponding to local minima at the more superior
B3LYP/6-31G(d,p) theoretical approach. The initial geometry of the IN/5CITEP
adduct was taken from Protein Data Bank (PDB, entry code 1QS4). Interestingly,
5CITEP in the complex with IN in the X-ray determined structure, differs slightly
from the equilibrium conformation of the free ligand, probably, due to additional
interactions arising between 5CITEP and the surrounding amino acids.
Seven different structures of the complex were generated including both neutral and deprotonated forms of 5CITEP as well as both neutral and protonated
forms of two lysines (Lys156 and Lys159) and then optimized by fixing the C α
atoms in the amino acids. The lowest energy structures for the protonated and noncharged states of the adduct are shown in Fig. 7.9. 5CITEP is in its neutral form,
where the hydrogen atom is attached to N3 of the tetrazole ring while Lys156
and Lys159 are non-protonated and protonated, respectively. The structure of the
A. B. Rozhenko
modeling the active site of HIV-1 IN were calculated. As objects for DFT calculations, the magnesium ions were surrounded with three formic acids and four water
molecules in order to mimic the IN binding site. In the optimized structures, the
most stable forms in water solution included deprotonated, enolized or phenolic
hydroxy groups, with the two eight-coordinated magnesium ions separated by a
distance 3.70–3.74 Å. Replacing one water in the complex with one molecule of
methanol mimiced the terminal 3′-OH of viral DNA, and the chelating complex
remained stable. Probably, after 3′-processing, in the binding site of IN the terminal
3′-OH of viral DNA interacts with one Mg
2 +
by chelation.
+
2
2
2
2+
+
+
2
2 +
2
1
1
+1
+
1
2
1
+1
2
)
&O
)
+
1
2
2+
2
2+
Wolschann et al. [103] used DFT calculations to identify the protonation state of
HIV-1 IN, in particular, residues Lys156 and Lys159, which are of importance for
binding 5CITEP inhibitor (88). The most favored conformations of 5CITEP were
derived at the B3LYP/6-31G(d,p) level of theory by a variation of two torsion angles, Tor1 (C19-C11-C9-C8) and Tor2 (N3-C5-C6-C8) (Fig. 7.8, left). The potential energy surface (PES) was analyzed at the HF/3-21G level with subsequent reoptimization of the structures corresponding to local minima at the more superior
B3LYP/6-31G(d,p) theoretical approach. The initial geometry of the IN/5CITEP
adduct was taken from Protein Data Bank (PDB, entry code 1QS4). Interestingly,
5CITEP in the complex with IN in the X-ray determined structure, differs slightly
from the equilibrium conformation of the free ligand, probably, due to additional
interactions arising between 5CITEP and the surrounding amino acids.
Seven different structures of the complex were generated including both neutral and deprotonated forms of 5CITEP as well as both neutral and protonated
forms of two lysines (Lys156 and Lys159) and then optimized by fixing the C α
atoms in the amino acids. The lowest energy structures for the protonated and noncharged states of the adduct are shown in Fig. 7.9. 5CITEP is in its neutral form,
where the hydrogen atom is attached to N3 of the tetrazole ring while Lys156
and Lys159 are non-protonated and protonated, respectively. The structure of the