Multi-shell model of ion-induced nucleic acid condensation

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• Multivalent ions like cobalt(iii) hexammine (CoHex) are known to induce condensation of nucleic acids (NA).
• Understanding the molecular mechanisms of NA condensation is crucial for various biological processes and nanotechnology applications.
• Previous models have not fully captured the nuanced interactions governing NA condensation, particularly the differences between DNA and RNA.

Purpose of the Study:

• To present a semi-quantitative model explaining the condensation of short nucleic acid (NA) duplexes mediated by trivalent cobalt(iii) hexammine (CoHex) ions.
• To elucidate the role of ion distribution and binding shells in NA duplex aggregation.
• To investigate the differential condensation propensities of DNA and RNA duplexes.

Main Methods:

• Developed a model based on partitioning counterion distribution around NA duplexes into 'external' and 'internal' binding shells.
• Incorporated overlapping shells in the aggregated phase to explain increased CoHex ion attraction between neighboring duplexes.
• Decomposed aggregation free energy into analytical expressions derived from molecular dynamics simulations and Poisson equation solutions.

Main Results:

• The model accurately estimates NA duplex aggregation free energy, consistent with experimental condensation propensities, including poor RNA condensation and sequence-dependent DNA condensation.
• Predicted that RNA duplexes may form tighter aggregates with higher neutralization compared to DNA.
• Showed that longer NA fragments condense more readily than shorter ones.

Conclusions:

• The proposed model, based on multivalent ion binding shells, successfully explains experimentally observed trends in NA condensation.
• CoHex-mediated attraction in RNA requires closer inter-duplex separation to engage ions primarily bound in the internal shell.
• The model provides a framework for understanding the fundamental principles governing multivalent ion-induced NA condensation.