Evaluating the role of coherent delocalized phonon-like modes in DNA cyclization

Ludmil B Alexandrov,Kim Ø Rasmussen,Alan R Bishop,Boian S Alexandrov

doi:10.1038/s41598-017-09537-y

Ludmil B Alexandrov, Kim Ø Rasmussen + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-09537-y

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Abstract

The innate flexibility of a DNA sequence is quantified by the Jacobson-Stockmayer’s J-factor, which measures the propensity for DNA loop formation. Recent studies of ultra-short DNA sequences revealed a discrepancy of up to six orders of magnitude between experimentally measured and theoretically predicted J-factors. These large differences suggest that, in addition to the elastic moduli of the double helix, other factors contribute to loop formation. Here, we develop a new theoretical model that explores how coherent delocalized phonon-like modes in DNA provide single-stranded ”flexible hinges” to assist in loop formation. We combine the Czapla-Swigon-Olson structural model of DNA with our extended Peyrard-Bishop-Dauxois model and, without changing any of the parameters of the two models, apply this new computational framework to 86 experimentally characterized DNA sequences. Our results demonstrate that the new computational framework can predict J-factors within an order of magnitude of experimental measurements for most ultra-short DNA sequences, while continuing to accurately describe the J-factors of longer sequences. Further, we demonstrate that our computational framework can be used to describe the cyclization of DNA sequences that contain a base pair mismatch. Overall, our results support the conclusion that coherent delocalized phonon-like modes play an important role in DNA cyclization.

Highlights

The flexibility of the DNA molecule plays an important role in a multitude of biological functions as well as in the compact storage of the genetic material of cells[1]
Without changing any of the original parameters in the CSO model or the Extended Peyrard-Bishop-Dauxois (EPBD) model, the coupled CSO-EPBD model is able to accurately determine the J-factors of ultra-short DNA sequences with most predictions being within an order of magnitude of experimental measurements
We developed a new theoretical model for describing DNA cyclization by combining the EPBD model with the CSO model

Summary

Introduction

The flexibility of the DNA molecule plays an important role in a multitude of biological functions as well as in the compact storage of the genetic material of cells[1]. Ignoring the 3D nature of DNA results in disregarding the proper torsional orientation of DNA segments, and does not allow describing the experimentally observed oscillations of the cyclization rates due to the approximately 10 bp torsional period of the double helix[31]. The lack of nucleotide sequence and intrinsic curvature information in the basic WLC model limits its predictive capability, since experimental studies have shown that periodic stretches of consecutive adenine-thymine base pairs possess curved equilibrium conformations[32]. To more realistically calculate cyclization properties of DNA, a coarse-grained Monte Carlo approach incorporating the 3D structure, intrinsic curvature, and DNA sequence was developed by Levenet, Crothers, and Zhang[36, 37], by Manning, Maddocks, and Kahn[38], and by Czapla, Swigon, and Olson[39]

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