40
M. P. Evstigneev and A. V. Shestopalova
2.4.3 Energy Analysis of Ligand-DNA Intercalation Reactions
To date the successful energy decomposition has been accomplished for wide variety of aromatic DNA intercalators [107, 117, 118]. We shall briefly review these
results taking as an example four typical aromatic drugs [107], viz. antibiotics,
daunomycin (DAU), mitoxantrone (NOV) and mutagens, ethidium bromide (EB),
proflavine (PF). The conclusions to be drawn for these ligands also remain essentially the same for other aromatic ligands investigated in the cited literature.
2.4.3.1 Structure of the DNA Receptor
Although the specificity of the aromatic molecules (EB, NOV, PF, DAU) to particular DNA sequences is not great, analysis of the literature suggests that the intercalator molecules not containing heavily-branched side chains commonly have some
specificity towards 5′-CG and 5′-GC sites [119, 120]. Also, taking into account that
DAU exerts greater specificity to CGA triplet sites on DNA rather than to CG or
GC dinucleotide sequences [121], it is reasonable to take the self-complementary
fragment, d(TCGA) 2 , flanked at both ends by CG pairs, as the minimal site for
ligand binding. Hence, the 10-mer oligonucleotide duplex, d(CGCTCGAGCG) 2 ,
was used as the model DNA receptor. It was shown that such length of DNA is long
enough for correct reproducing of electrostatic interaction for the group of aromatic
intercalators [122].
2.4.3.2 Van der Waals Energy, ΔG vdW
The MD averaged van der Waals energies in the selected ligand-DNA complexes
are presented in Table 2.1.
The intramolecular energies of DNA base pairs interaction, ∆G conf
im
, at the stage of
unwinding are all positive, which is a result of separation of base pairs upon formation of the intercalation cavity. The energies of the solvation of the intercalation site,
∆G conf
solv
, are all negative and result from hydration of the intercalation cavity upon
DNA unwinding.
At the stage of ligand insertion the intermolecular energy of ligand-DNA interaction,
im
ins
G
∆
, has a negative sign, which results from the attractive nature of VDW
forces acting between the ligand and DNA base pairs within the intercalation site.
The positive VDW energy of the interaction with solvent,
solv
ins
G
∆
, is due to dehydration of the ligand after its insertion into DNA interior.
The total VDW energy of insertion,
ins
G
∆ , is a relatively small value and is a
result of mutual compensation from favourable intermolecular interaction between
DNA and the ligand, and unfavourable interaction with the solvent. The compensation may lead to positive (PF) and negative (DAU, EB, NOV) ∆G vdw
ins
(see Table 2.1)
which means that VDW interactions at the stage of insertion may either favour or
M. P. Evstigneev and A. V. Shestopalova
2.4.3 Energy Analysis of Ligand-DNA Intercalation Reactions
To date the successful energy decomposition has been accomplished for wide variety of aromatic DNA intercalators [107, 117, 118]. We shall briefly review these
results taking as an example four typical aromatic drugs [107], viz. antibiotics,
daunomycin (DAU), mitoxantrone (NOV) and mutagens, ethidium bromide (EB),
proflavine (PF). The conclusions to be drawn for these ligands also remain essentially the same for other aromatic ligands investigated in the cited literature.
2.4.3.1 Structure of the DNA Receptor
Although the specificity of the aromatic molecules (EB, NOV, PF, DAU) to particular DNA sequences is not great, analysis of the literature suggests that the intercalator molecules not containing heavily-branched side chains commonly have some
specificity towards 5′-CG and 5′-GC sites [119, 120]. Also, taking into account that
DAU exerts greater specificity to CGA triplet sites on DNA rather than to CG or
GC dinucleotide sequences [121], it is reasonable to take the self-complementary
fragment, d(TCGA) 2 , flanked at both ends by CG pairs, as the minimal site for
ligand binding. Hence, the 10-mer oligonucleotide duplex, d(CGCTCGAGCG) 2 ,
was used as the model DNA receptor. It was shown that such length of DNA is long
enough for correct reproducing of electrostatic interaction for the group of aromatic
intercalators [122].
2.4.3.2 Van der Waals Energy, ΔG vdW
The MD averaged van der Waals energies in the selected ligand-DNA complexes
are presented in Table 2.1.
The intramolecular energies of DNA base pairs interaction, ∆G conf
im
, at the stage of
unwinding are all positive, which is a result of separation of base pairs upon formation of the intercalation cavity. The energies of the solvation of the intercalation site,
∆G conf
solv
, are all negative and result from hydration of the intercalation cavity upon
DNA unwinding.
At the stage of ligand insertion the intermolecular energy of ligand-DNA interaction,
im
ins
G
∆
, has a negative sign, which results from the attractive nature of VDW
forces acting between the ligand and DNA base pairs within the intercalation site.
The positive VDW energy of the interaction with solvent,
solv
ins
G
∆
, is due to dehydration of the ligand after its insertion into DNA interior.
The total VDW energy of insertion,
ins
G
∆ , is a relatively small value and is a
result of mutual compensation from favourable intermolecular interaction between
DNA and the ligand, and unfavourable interaction with the solvent. The compensation may lead to positive (PF) and negative (DAU, EB, NOV) ∆G vdw
ins
(see Table 2.1)
which means that VDW interactions at the stage of insertion may either favour or