Molecular models for intrastrand DNA G-quadruplexes

We have used all quadruplex DNA structures deposited in the Nucleic Acid Database in order to select a list of fragments entailing a strand of three adjacent G's paired with another strand of three adjacent G's separated by a loop of one to four residues. These fragments were further clustered and representative fragments were finally selected. Further fragments were generated by assemblying the two strands of each fragment with loops from different fragments whenever the anchor G's were superimposable. The fragments were used to assemble G quadruplex based on a superimposability criterion.Molecular models have been generated for a large number of G3Xn1G3Xn2G3Xn3G3 sequences. For a given sequence not all topologies are possible with the available repertoire of fragments due to steric hindrance and low superimposability. Since all molecular models are generated by fragments coming from observed quadruplex structures, molecular models are in principle reliable and may be used for interpretation of experimental data. Some examples of applications are given.It is generally recognized that in addition to the canonical Watson-Crick double-stranded conformation, DNA can assume a variety of secondary structures including triplex [1-3], cruciform [4], quadruplex [5-7] and Z-DNA [8]. Quadruplex DNA, also called G4-DNA, is stabilized by G-quartets, planar arrays of four guanines paired by Hoogsteen hydrogen bonding, and monovalent alkali cation, K+ or Na+, located in the central cavity of the structure. G-quartets can stabilize a variety of quadruplex structures which can be intermolecular or intramolecular, in which single-stranded DNA is folded to provide the four strands of the guanine scaffold. In the human genome the sites that can potentially form G4-DNA are estimated to be more than 300.000. They are not randomly distributed, but located preferentially in repetitive genomic sequences such as the telomeres, ribosomal DNA and the immunoglobulin heavy-chain switch regions