Abstract

Hoogsteen (HG) base-pairing is characterized by a 180° rotation of the purine base with respect to the Watson-Crick-Franklin (WCF) motif. Recently, it has been found that both conformations coexist in a dynamical equilibrium and that several biological functions require HG pairs. This relevance has motivated experimental and computational investigations of the base-pairing transition. However, a systematic simulation of sequence variations has remained out of reach. Here, we employ advanced path-based methods to perform unprecedented free-energy calculations. Our methodology enables us to study the different mechanisms of purine rotation, either remaining inside or after flipping outside of the double helix. We study seven different sequences, which are neighbor variations of a well-studied A·T pair in A6-DNA. We observe the known effect of A·T steps favoring HG stability, and find evidence of triple-hydrogen-bonded neighbors hindering the inside transition. More importantly, we identify a dominant factor: the direction of the A rotation, with the 6-ring pointing either towards the longer or shorter segment of the chain, respectively relating to a lower or higher barrier. This highlights the role of DNA's relative flexibility as a modulator of the WCF/HG dynamic equilibrium. Additionally, we provide a robust methodology for future HG proclivity studies.

Competing Interest Statement

The authors have declared no competing interest.

Details

Title
Sequence dependence of transient Hoogsteen base-pairing in DNA
Author
Alberto Pérez De Alba Ortíz; Vreede, Jocelyne; Ensing, Bernd
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2021
Publication date
Aug 4, 2021
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2557923506
Copyright
© 2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.