Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Polyethylene glycols (PEGs) are commonly used to alter nucleic acid conformations.
• The precise mechanism by which PEGs induce these conformational changes, particularly in G-quadruplexes, remains unclear.

Purpose of the Study:

• To investigate how Polyethylene glycols (PEGs) and other co-solutes affect the conformation of the human telomeric G-quadruplex.
• To elucidate the underlying mechanism of PEG-induced conformational changes in G-quadruplexes.

Main Methods:

• Osmotic stress studies using acetonitrile and ethylene glycol.
• Sedimentation velocity experiments.
• Polyethylene glycol (PEG) titration experiments and molecular dynamics simulations.

Main Results:

• Conversion to the propeller conformation releases water and is energetically unfavorable in aqueous solutions.
• The propeller form is hydrodynamically larger, excluding a crowding mechanism for PEG.
• PEG titration favors a conformational selection mechanism, with PEG binding coupled to the transition.

Conclusions:

• Polyethylene glycols (PEGs) do not function via a crowding mechanism to alter G-quadruplex conformation.
• PEG binding is most consistent with conformational selection, favoring the propeller form.
• PEG is not an accurate mimic of the intranuclear environment for studying G-quadruplexes.