Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose)

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Poly(ADP-ribose) (PAR) is a non-canonical nucleic acid vital for DNA/RNA metabolism and protein condensation.
• Dysregulation of PAR is implicated in diseases like cancer and neurodegeneration.
• Understanding PAR's structure-function relationship is limited by synthesis and characterization challenges, particularly its length heterogeneity.

Purpose of the Study:

• To investigate the structural basis of Poly(ADP-ribose) (PAR) specificity in protein binding and condensation.
• To elucidate how PAR chain length influences its structural ensembles and compaction.
• To characterize the distinct structural behaviors of different PAR lengths upon ion addition.

Main Methods:

• Integration of molecular dynamics (MD) simulations.
• Analysis using small-angle X-ray scattering (SAXS).
• Characterization of PAR structures across varying lengths and in the presence of Mg²⁺ ions.

Main Results:

• Identification of diverse structural ensembles for PAR, falling into distinct subclasses.
• Observation of differential compaction for PAR chains of different lengths (e.g., PAR₁₅ vs. PAR₂₂) upon addition of Mg²⁺.
• PAR₂₂ exhibits ADP-ribose bundling via intramolecular coil-to-globule transitions, distinct from PAR₁₅.

Conclusions:

• PAR's structure is highly dependent on its chain length.
• Length-specific structural changes, such as bundling and compaction, are critical for PAR's biological functions.
• Deciphering these length-dependent structural dynamics is key to understanding PAR's roles in cellular processes and disease pathogenesis.