26
M. P. Evstigneev and A. V. Shestopalova
of cooperative units, which melt according to the two-state model. Explicit account
of ligand distribution on polymeric DNA and the temperature dependencies of melting and binding constants, as well as enthalpies, were considered. Such approach
enables to extract the binding constant, stoichiometry, enthalpy, entropy, and heat
capacity changes from multiple excess heat capacity profiles obtained at varying
concentrations of the ligand (i.e. the two-dimensional DSC curves). Comparison of
the binding parameters calculated by fitting of two-dimensional DSC curves with
the literature data and with that obtained by alternative experimental techniques,
had demonstrated that the approach presented in [64] gives satisfactory results.
2.2.5 Computer Modeling
Binding affinity of the ligands with DNA may be estimated at the molecular level
based on shape complementarity of the interacting parts of the ligands and DNA,
and by explicit consideration of physical interactions (electrostatic, van der Waals,
hydrophobic, specific hydrogen bonding etc.). It allows to determine the extent to
which the formation of the complex under investigation is energetically favourable. However, all microscopic details of the interaction cannot be identified in
experiment. In such case computer simulations are commonly used as an appropriate complementary tool for modeling atomic-level interactions that produces the
data about the structure of the most probable DNA—ligand complexes and on the
contributions of different interactions to their stabilization with explicit account of
water environment [65–71].
Molecular docking method is one of the most effective computer simulation
methods, making possible a fast re-construction of all possible configurations of
complexes between biological macromolecule and the ligand of interest. The molecular docking method is commonly used for estimation of specifity of protein–
ligand interactions [72–74]. The docking of ligands to DNA molecules is a less
frequently used approach. In this approach anticancer drugs are usually taken as
the ligands [75]. In order to investigate their complexes by computer simulation,
the initial coordinates must be known. If the structure of the complex under study
is absent in structural databases, the investigator often faces a difficulty on how to
create the binding site. The results of docking of the ligands with different DNAtargets indicate [76] that upon formation of the intercalation site it is usually enough
to take into account only the most significant unwinding in one particular helical
step or in the adjacent helical step of DNA double helix. The magnitude of the total
unwinding of the DNA in the intercalation complex was found to be dependent on
the sequence and length of the target DNA.
The application of Monte Carlo method for the study of hydration of nucleic
acids, their components [77–80], and hydration of the DNA-ligand complexes (for
example, dCpG with proflavine [81] and DNA with azinomycin B [82] intercalated
complexes) was described in literature in detail. Monte Carlo simulations enable to
evaluate the low energy conformations of various complexes of DNA fragments,
M. P. Evstigneev and A. V. Shestopalova
of cooperative units, which melt according to the two-state model. Explicit account
of ligand distribution on polymeric DNA and the temperature dependencies of melting and binding constants, as well as enthalpies, were considered. Such approach
enables to extract the binding constant, stoichiometry, enthalpy, entropy, and heat
capacity changes from multiple excess heat capacity profiles obtained at varying
concentrations of the ligand (i.e. the two-dimensional DSC curves). Comparison of
the binding parameters calculated by fitting of two-dimensional DSC curves with
the literature data and with that obtained by alternative experimental techniques,
had demonstrated that the approach presented in [64] gives satisfactory results.
2.2.5 Computer Modeling
Binding affinity of the ligands with DNA may be estimated at the molecular level
based on shape complementarity of the interacting parts of the ligands and DNA,
and by explicit consideration of physical interactions (electrostatic, van der Waals,
hydrophobic, specific hydrogen bonding etc.). It allows to determine the extent to
which the formation of the complex under investigation is energetically favourable. However, all microscopic details of the interaction cannot be identified in
experiment. In such case computer simulations are commonly used as an appropriate complementary tool for modeling atomic-level interactions that produces the
data about the structure of the most probable DNA—ligand complexes and on the
contributions of different interactions to their stabilization with explicit account of
water environment [65–71].
Molecular docking method is one of the most effective computer simulation
methods, making possible a fast re-construction of all possible configurations of
complexes between biological macromolecule and the ligand of interest. The molecular docking method is commonly used for estimation of specifity of protein–
ligand interactions [72–74]. The docking of ligands to DNA molecules is a less
frequently used approach. In this approach anticancer drugs are usually taken as
the ligands [75]. In order to investigate their complexes by computer simulation,
the initial coordinates must be known. If the structure of the complex under study
is absent in structural databases, the investigator often faces a difficulty on how to
create the binding site. The results of docking of the ligands with different DNAtargets indicate [76] that upon formation of the intercalation site it is usually enough
to take into account only the most significant unwinding in one particular helical
step or in the adjacent helical step of DNA double helix. The magnitude of the total
unwinding of the DNA in the intercalation complex was found to be dependent on
the sequence and length of the target DNA.
The application of Monte Carlo method for the study of hydration of nucleic
acids, their components [77–80], and hydration of the DNA-ligand complexes (for
example, dCpG with proflavine [81] and DNA with azinomycin B [82] intercalated
complexes) was described in literature in detail. Monte Carlo simulations enable to
evaluate the low energy conformations of various complexes of DNA fragments,