Sequence dependence of transient Hoogsteen base pairing in DNA

• DOI: 10.1371/journal.pcbi.1010113
• Publication Date: 2022-05-26T17:54:18Z
• Authors: Alberto Pérez de ...; Jocelyne Vreede; Bernd Ensing
• Keywords: Sequence (biology)

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