DNA denaturation bubbles: free-energy landscape and nucleation/closure rates

TL;DR

This study uses coarse-grained simulations to analyze the free-energy landscape and kinetics of DNA denaturation bubbles, revealing the key role of torsional energy and collective twisting in nucleation and closure processes.

Contribution

It introduces a minimal mesoscopic model combined with MetaDynamics to accurately characterize the free-energy barriers and timescales of DNA bubble nucleation and closure.

Findings

Nucleation and closure times match experimental data.

Free-energy barriers are mainly due to torsional energy differences.

Collective twisting is the limiting step in bubble dynamics.

Abstract

The issue of the nucleation and slow closure mechanisms of non superhelical stress-induced denaturation bubbles in DNA is tackled using coarse-grained MetaDynamics and Brownian simulations. A minimal mesoscopic model is used where the double helix is made of two interacting bead-spring rotating strands with a prescribed torsional modulus in the duplex state. We demonstrate that timescales for the nucleation (resp. closure) of an approximately 10 base-pair bubble, in agreement with experiments, are associated with the crossing of a free-energy barrier of $22~k_{\rm B}T$ (resp. $13~k_{\rm B}T$) at room temperature $T$. MetaDynamics allows us to reconstruct accurately the free-energy landscape, to show that the free-energy barriers come from the difference in torsional energy between the bubble and duplex states, and thus to highlight the limiting step, a collective twisting, that controls the nucleation/closure mechanism, and to access opening time scales on the millisecond range. Contrary to small breathing bubbles, these more than 4~base-pair bubbles are of biological relevance, for example when a preexisting state of denaturation is required by specific DNA-binding proteins.