Implications for the Folding Pathway

The thermodynamic, kinetic and structural data presented above give some indications about the folding pathway required to form G-quadruplexes. In terms of folding intermediates, the best-studied systems concern tetramolecular quadruplexes. Several experimental and theoretical studies provide clues on the possible ways to a fully formed quadruplex. 

We and others have demonstrated that association of short strands containing a single guanine-repeat seems to obey a fourth-order kinetics model. Third or fourth-order reactions are not common in biochemistry, and the practical consequences of this reaction order are important. A fourth-order reaction does not imply that an elementary kinetic step involves a four-body collision. Such mechanism is extremely unlikely and other processes could lead to this fourth order. The structure of these elusive intermediates remains unknown Stefl et have recently demonstrated that a Hoogsteen G-G duplex is an improbable intermediate. Its identification will be experimentally difficult, as numerical simulations indicate that it may not be present at detectable levels. 

---