Consequences of local inter-strand dehybridization for large-amplitude bending fluctuations of double-stranded DNA

TL;DR

This study investigates how local disruptions in DNA base pairing, modeled as 'melts' or 'kinks', influence the molecule's flexibility and cyclization behavior, especially in very short DNA chains, using advanced simulations.

Contribution

The paper introduces a thermodynamically consistent model of meltable wormlike chains and applies a novel simulation method to analyze their cyclization properties across various lengths.

Findings

Melting excitations minimally affect longer DNA chains' cyclization.

Significant melting effects are observable only in very short DNA molecules.

New computational approach enables analysis of short-chain DNA cyclization.

Abstract

The wormlike chain (WLC) model of DNA bending accurately reproduces single-molecule force-extension profiles of long (kilobase) chains. These bending statistics over large scales do not, however, establish a unique microscopic model for elasticity at the 1-10 bp scale, which holds particular interest in biological contexts. Here we examine a class of microscopic models which allow for disruption of base pairing (i.e., a `melt' or `kink', generically an `excitation') and consequently enhanced local flexibility. We first analyze the effect on the excitation free energy of integrating out the spatial degrees of freedom in a wormlike chain. Based on this analysis, we present a formulation of these models that ensures consistency with the well-established thermodynamics of melting in long chains. Using a new method to calculate cyclization statistics of short chains from enhanced-sampling Monte Carlo simulations, we compute J-factors of a meltable wormlike chain (MWLC) over a broad range of chain lengths, including very short molecules (30 bp) that have not yet been explored experimentally. For chains longer than about 120 bp, including most molecules studied to date in the laboratory, we find that melting excitations have little impact on cyclization kinetics. Strong signatures of melting, which might be resolved within typical experimental scatter, emerge only for shorter chains.