Identifying Physical Causes of Apparent Enhanced Cyclization of Short DNA Molecules with a Coarse-Grained Model

Abstract

DNA cyclization is a powerful technique to gain insight into the nature of DNA bending. While the wormlike chain model provides a good description of small to moderate bending fluctuations, it is expected to break down for large bending. Recent cyclization experiments on strongly bent shorter molecules indeed suggest enhanced flexibility over and above that expected from the wormlike chain. Here, we use a coarse-grained model of DNA to investigate the subtle thermodynamics of DNA cyclization for molecules ranging from 30 to 210 base pairs. As the molecules get shorter, we find increasing deviations between our computed equilibrium j -factor and the classic wormlike chain predictions of Shimada and Yamakawa for a torsionally aligned looped molecule. These deviations are due to sharp kinking, first at nicks, and only subsequently in the body of the duplex. At the shortest lengths, substantial fraying at the ends of duplex domains is the dominant method of relaxation. We also estimate the dynamic j -factor measured in recent FRET experiments. We find that the dynamic j -factor is systematically larger than its equilibrium counterpart—with the deviation larger for shorter molecules—because not all the stress present in the fully cyclized state is present in the transition state. These observations are important for the interpretation of recent cyclization experiments, suggesting that measured anomalously high j -factors may not necessarily indicate non-WLC behavior in the body of duplexes.

Coarse-Grained Modelling of DNA Plectoneme Pinning in the Presence of Base-Pair Mismatches

“…All the simulations presented in the current paper are performed using the sequence dependent variation of the OxDNA model 39 implemented in the LAMMPS 46 simulation software by Henrich et al 40 . The OxDNA model has previously been shown to reproduce the behavior of DNA under tension and torsional stress 33 and has also been used to study various structural features of DNA 41,[47][48][49][50] . In the following sections the simulation parameters are given in the reduced…”

A molecular view of DNA flexibility

“…DNA kinks were predicted long ago (Crick and Klug, 1975) and have been observed in crystal structures of a number of DNA:protein complexes (Berman et al ., 1992; Olson et al, 1998), including nucleosomal DNA (Olson and Zhurkin, 2011); and also in several MD simulations (Lankaš et al , 2006; Curuksu et al ., 2009; Irobalieva et al ., 2015; Harrison et al ., 2019). The biological consequences of DNA kinks are diverse, and have been reviewed in the context of DNA wrapping in the nucleosome core (Richmond and Davey, 2003; Olson and Zhurkin, 2011) and of specific DNA:protein interactions (Rohs et al ., 2010).…”

A Primer on the oxDNA Model of DNA: When to Use it, How to Simulate it and How to Interpret the Results

“…The oxDNA model, first published in 2010 ( Ouldridge et al, 2010a ) (and with a slightly updated potential in 2011 ( Ouldridge et al, 2011 )), has now been extensively applied to problems in nanotechnology ( Ouldridge et al, 2013a ; Doye et al, 2013 ; Srinivas et al, 2013 ; Machinek et al, 2014 ; Snodin et al, 2016 , 2019 ; Henning-Knechtel et al, 2017 ; Hong et al, 2018 ), soft matter ( De Michele et al, 2012 ; Rovigatti et al, 2014 ; Procyk et al, 2020 ; Stoev et al, 2020 ), biophysics ( Matek et al, 2012 ; Romano et al, 2013 ; Matek et al, 2015 ; Mosayebi et al, 2015 ; Harrison et al, 2019 ; Nomidis et al, 2019 ) and biology ( Lee et al, 2015 ; Wang et al, 2015 ; Craggs et al, 2019 ). Numerous tools exist to generate and visualize systems with oxDNA ( Henrich et al, 2018 ; Suma et al, 2019 ), alongside two independent, publicly-available code bases for actually running simulations with at least three qualitatively distinct algorithms for simulating the model ( Ouldridge et al, 2011 ; Snodin et al, 2015 ).…”