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

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 $22k_{\mathrm{B}}T$ (resp. $13k_{\mathrm{B}}T$) 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.

arXiv comment11 pages (5 pages and Appendix), 13 figures, published in Journal of Chemical Physics

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• A Single Nucleotide Resolution Model for Large-Scale Simulations of Double Stranded DNA
• Computing Transition Rates for Rare Event: When Kramers Theory meets Free Energy Landscape
• Efimov like phase of a three stranded DNA (Efimov-DNA) and the renormalization group limit cycle
• Elasticity of a DNA chain dotted with bubbles under force