187
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
6.3.2 Quantum Chemical Calculations on G-Quadruplexes
Recent advances in computational processing power and modelling algorithms
have resulted in the development of new efficient computer-aided methods for the
discovery of novel drugs interacting with biomacromolecules. The availability of
crystallographic and NMR data for G4 structures strongly facilitates the design of
potent antitumor compounds using computational methods.
6.3.2.1 G-Quadruplex Structures and Ligand Binding
Despite recent theoretical advances, the complexity of quadruplex architectures remains a great challenge for computer modelling of G4 and their complexes. One
of the main problems for any molecular modelling approach is unusually broad
structural polymorphism of quadruplex DNA. This polymorphism results mainly
from the conformational flexibility of DNA chains and non-covalent (hydrophobic, stacking, electrostatic) interactions of quadruplex fragments, both heterocyclic
nucleic bases and sugar-phosphate backbone. There are intra- and intermolecular
(dimeric, tetrameric) quadruplexes, with parallel, antiparallel or mixed (hybrid)
type of G4 structures. The geometric parameters of guanine quartets may differ to
some extent as well. The topology of a quadruplex is determined by a number of
factors, including e.g. nucleotide sequence, pH, the nature (Na
+
, K
+
or NH 4
+
) and
concentration of cations present in the medium, etc. Moreover, depending on the
conditions the same nucleic acid sequence may form several quadruplex structures
with different conformations, or their equilibrium mixtures [5, 7, 10–15, 37–43,
69–72]. It is widely accepted that the crystal (X-ray) and solution (determined by
NMR) structures may be also different for the same oligonucleotide sequence [38,
72, 73]. Some examples of diverse quadruplex topologies are presented in Fig. 6.3.
To understand the functioning of G-quadruplexes and its recognition by small
molecules, a deep analysis of structural and energetic properties of G4 fragments,
first of all guanine quartets and their stacks as a key element of quadruplex structures, is required.
In general, there are several possible binding modes for quadruplex ligands: they
can stack externally upon a terminal G-quartet (mainly via π-π interactions), intercalate between two G-quartets, and bind to the quadruplex grooves between two adjacent DNA chains. Additional electrostatic interaction of a ligand with phosphate
groups, most often provided by basic/cationic side chains, is usually required to
ensure high binding affinity. Ligand interaction with quadruplex loops may further
increase the binding specificity [5, 7, 10, 12, 21–23]. Taking into account the structural diversity and polymorphism of quadruplex structures, design of efficient G4
ligands is a complicated and challenging task, especially when specific binding to a
particular topologic form of a quadruplex should be achieved.
Nevertheless, all forms of quadruplexes have common structural elements as
these assemblies are formed by DNA chains and contain the stacks of G-quartets.
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
6.3.2 Quantum Chemical Calculations on G-Quadruplexes
Recent advances in computational processing power and modelling algorithms
have resulted in the development of new efficient computer-aided methods for the
discovery of novel drugs interacting with biomacromolecules. The availability of
crystallographic and NMR data for G4 structures strongly facilitates the design of
potent antitumor compounds using computational methods.
6.3.2.1 G-Quadruplex Structures and Ligand Binding
Despite recent theoretical advances, the complexity of quadruplex architectures remains a great challenge for computer modelling of G4 and their complexes. One
of the main problems for any molecular modelling approach is unusually broad
structural polymorphism of quadruplex DNA. This polymorphism results mainly
from the conformational flexibility of DNA chains and non-covalent (hydrophobic, stacking, electrostatic) interactions of quadruplex fragments, both heterocyclic
nucleic bases and sugar-phosphate backbone. There are intra- and intermolecular
(dimeric, tetrameric) quadruplexes, with parallel, antiparallel or mixed (hybrid)
type of G4 structures. The geometric parameters of guanine quartets may differ to
some extent as well. The topology of a quadruplex is determined by a number of
factors, including e.g. nucleotide sequence, pH, the nature (Na
+
, K
+
or NH 4
+
) and
concentration of cations present in the medium, etc. Moreover, depending on the
conditions the same nucleic acid sequence may form several quadruplex structures
with different conformations, or their equilibrium mixtures [5, 7, 10–15, 37–43,
69–72]. It is widely accepted that the crystal (X-ray) and solution (determined by
NMR) structures may be also different for the same oligonucleotide sequence [38,
72, 73]. Some examples of diverse quadruplex topologies are presented in Fig. 6.3.
To understand the functioning of G-quadruplexes and its recognition by small
molecules, a deep analysis of structural and energetic properties of G4 fragments,
first of all guanine quartets and their stacks as a key element of quadruplex structures, is required.
In general, there are several possible binding modes for quadruplex ligands: they
can stack externally upon a terminal G-quartet (mainly via π-π interactions), intercalate between two G-quartets, and bind to the quadruplex grooves between two adjacent DNA chains. Additional electrostatic interaction of a ligand with phosphate
groups, most often provided by basic/cationic side chains, is usually required to
ensure high binding affinity. Ligand interaction with quadruplex loops may further
increase the binding specificity [5, 7, 10, 12, 21–23]. Taking into account the structural diversity and polymorphism of quadruplex structures, design of efficient G4
ligands is a complicated and challenging task, especially when specific binding to a
particular topologic form of a quadruplex should be achieved.
Nevertheless, all forms of quadruplexes have common structural elements as
these assemblies are formed by DNA chains and contain the stacks of G-quartets.