Cooperativity-Dependent Folding of Single-Stranded DNA

TL;DR

This study introduces a helix-coil model for ssDNA folding that accurately predicts secondary structure formation and energetics under various conditions, enhancing understanding of DNA folding mechanisms.

Contribution

The paper presents a novel helix-coil model for ssDNA folding that accounts for cooperativity and salt effects, validated against experimental force-extension data.

Findings

Model reproduces experimental force-extension curves.

Salt effects on folding energies are consistent with DNA hybridization.

Predicts folding free energy and domain sizes matching secondary structure predictions.

Abstract

The folding of biological macromolecules is a fundamental process of which we lack a full comprehension. Mostly studied in proteins and RNA, single-stranded DNA (ssDNA) also folds, at physiological salt conditions, by forming non-specific secondary structures that are difficult to characterize with biophysical techniques. Here we present a helix-coil model for secondary structure formation, where ssDNA bases are organized in two different types of domains (compact and free). The model contains two parameters: the energy gain per base in a compact domain, $\epsilon$, and the cooperativity related to the interfacial energy between different domains, $\gamma$. We tested the ability of the model to quantify the formation of secondary structure in ssDNA molecules mechanically stretched with optical tweezers. The model reproduces the experimental force-extension curves in ssDNA of different molecular lengths and varying sodium and magnesium concentrations. Salt-correction effects for the energy of compact domains and the interfacial energy are found to be compatible with those of DNA hybridization. The model also predicts the folding free energy and the average size of domains at zero force, finding good agreement with secondary structure predictions by Mfold. We envision the model could be further extended to investigate native folding in RNA and proteins.