185
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
than that required for common duplex DNA binding compounds. Only in this case
G4 ligand would be able to ensure an efficient overlap with guanine tetrad and
thus provide good quadruplex selectivity of the drug over the duplex DNA [7, 21,
22]. From this point of view, large ligands like porphyrins and telomestatin may be
preferable as their molecules perfectly overlap with G-tetrads. At the same time,
relatively small size of the central aromatic core can be efficiently compensated by
the substituents of cationic nature.
There are numerous experimental methods to investigate quadruplex DNA and
monitor and quantify its interactions with low-molecular ligands [24–26]. Besides
biochemical and electrophoretic methods [27], various biophysical approaches
are available, including e.g. absorption spectroscopy [28, 29], circular dichroism
spectroscopy [29, 30], fluorescence resonance energy transfer (FRET) [31, 32],
fluorescence melting assays [33] and other fluorescence-based techniques, and
mass spectrometry [25]. Another popular approach for studying biomolecular interactions in G-quadruplexes is surface plasmon resonance (SPR) [34–36]. These
methods provide valuable and diverse structural, kinetic and thermodynamic data.
At the same time, the main sources of precise structural information on
G-quadruplexes and their complexes with small molecules are X-ray crystallography [37–41] and NMR spectrometry [38, 42, 43]. Dozens of 3D structures of various forms of quadruplexes are currently available from Protein Data Bank and other
sources. These crystallographic or NMR structures are of great importance as they
are the basis for molecular modelling and modern drug design.
6.3 Theoretical Studies on G-Quadruplex Structures
and Their Interactions With Low-Molecular Ligands
The accurate modelling of the structures of biomacromolecules and their complexes
with small molecules and determining their thermodynamic parameters is still a
complicated and challenging problem due to the large size and complexity of molecular systems. Nevertheless, computer modelling of the structures of nucleic acids
and proteins and their interaction with low-molecular ligands is now an integral
part of drug design. Molecular modelling based on docking or molecular dynamics is very common in this field. At the same time, quantum chemical (quantum
mechanical) approaches are not so common; however, they are able to provide information that cannot be obtained by the other methods.
6.3.1 Computer Modelling Methods in the Study
of Biomacromolecules
In general, computational approaches to modelling a molecular system may be
divided into two broad categories: quantum mechanics (QM) [44] and molecular
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
than that required for common duplex DNA binding compounds. Only in this case
G4 ligand would be able to ensure an efficient overlap with guanine tetrad and
thus provide good quadruplex selectivity of the drug over the duplex DNA [7, 21,
22]. From this point of view, large ligands like porphyrins and telomestatin may be
preferable as their molecules perfectly overlap with G-tetrads. At the same time,
relatively small size of the central aromatic core can be efficiently compensated by
the substituents of cationic nature.
There are numerous experimental methods to investigate quadruplex DNA and
monitor and quantify its interactions with low-molecular ligands [24–26]. Besides
biochemical and electrophoretic methods [27], various biophysical approaches
are available, including e.g. absorption spectroscopy [28, 29], circular dichroism
spectroscopy [29, 30], fluorescence resonance energy transfer (FRET) [31, 32],
fluorescence melting assays [33] and other fluorescence-based techniques, and
mass spectrometry [25]. Another popular approach for studying biomolecular interactions in G-quadruplexes is surface plasmon resonance (SPR) [34–36]. These
methods provide valuable and diverse structural, kinetic and thermodynamic data.
At the same time, the main sources of precise structural information on
G-quadruplexes and their complexes with small molecules are X-ray crystallography [37–41] and NMR spectrometry [38, 42, 43]. Dozens of 3D structures of various forms of quadruplexes are currently available from Protein Data Bank and other
sources. These crystallographic or NMR structures are of great importance as they
are the basis for molecular modelling and modern drug design.
6.3 Theoretical Studies on G-Quadruplex Structures
and Their Interactions With Low-Molecular Ligands
The accurate modelling of the structures of biomacromolecules and their complexes
with small molecules and determining their thermodynamic parameters is still a
complicated and challenging problem due to the large size and complexity of molecular systems. Nevertheless, computer modelling of the structures of nucleic acids
and proteins and their interaction with low-molecular ligands is now an integral
part of drug design. Molecular modelling based on docking or molecular dynamics is very common in this field. At the same time, quantum chemical (quantum
mechanical) approaches are not so common; however, they are able to provide information that cannot be obtained by the other methods.
6.3.1 Computer Modelling Methods in the Study
of Biomacromolecules
In general, computational approaches to modelling a molecular system may be
divided into two broad categories: quantum mechanics (QM) [44] and molecular