Computational investigation of the impact of core sequence on immobile DNA four-way junction structure and dynamics

Abstract

Immobile four-way junctions (4WJs) are core structural motifs employed in the design of programmed DNA assemblies. Understanding the impact of sequence on their equilibrium structure and flexibility is important to informing the design of complex DNA architectures. While core junction sequence is known to impact the preferences for the two possible isomeric states that junctions reside in, previous investigations have not quantified these preferences based on molecular-level interactions. Here, we use all-atom molecular dynamics simulations to investigate base-pair level structure and dynamics of four-way junctions, using the canonical Seeman J1 junction as a reference. Comparison of J1 with equivalent single-crossover topologies and isolated nicked duplexes reveal conformational impact of the double-crossover motif. We additionally contrast J1 with a second junction core sequence termed J24, with equal thermodynamic preference for each isomeric configuration. Analyses of the base-pair degrees of freedom for each system, free energy calculations, and reduced-coordinate sampling of the 4WJ isomers reveal the significant impact base sequence has on local structure, isomer bias, and global junction dynamics.

Molecular dynamics simulations of cyanine dimers attached to DNA Holliday junctions

“…Furthermore, MD simulations of Holliday junctions have also been performed. 44,[57][58][59] Mathur et al has showed that MD simulations of dyes attached to the Holliday junctions of large DNA bundles can yield dye orientations in agreement with experimental uorescence data. 44 Wheatley et al found that isolated, four-arm Holliday junctions initialized in an open conformation stabilize in a stacked conguration at both high and low salt concentrations, indicating that MD is able to capture the conformational transitions of the Holliday junction.…”

“…Typical Holliday junction IDAs and twist angles fall in the range of ∼60° and ∼40–60°, respectively. 57–59,82 It should be noted that these values are for Holliday junctions without dyes attached to the DNA backbone – the dyes in our study act as an additional base or spacer in the DNA sequence, which may affect the DNA dynamics and conformations. This could lead to discrepancies observed between pure DNA Holliday junctions and Holliday junctions with dyes.…”

“… 58 Adendorff et al utilized MD to study the structure and dynamics of four-arm isolated Holliday junctions to understand the impact of base sequences on the junction structure. 59 However, the role of the DNA Holliday junction conformations and the interactions between the DNA and dyes that affect dye orientations and resultant excitonic properties are not fully understood.…”

Spectroscopic details on the molecular structure of pyrimidine‑2‑thiones heterocyclic compounds: computational and antiviral activity against the main protease enzyme of SARS-CoV-2

“…Theoretical computational guides highlight an important role in investigating the molecular structure and electronic properties of a wide range of highly functionalized systems [1][2][3][4]. The detailed computational experience was taken from using the most advanced wave function methods such as the most popular one, density functional theory (DFT).…”

“…The detailed computational experience was taken from using the most advanced wave function methods such as the most popular one, density functional theory (DFT). For highly functionalized systems such as pyridopyrimidines [1,2,[4][5][6] triazole, and [1][2][3][4] tetrazole derivatives, these types of compounds are interesting for different biological applications such as anti-microbial and cytotoxic activities [7]. Several studies are concerned with the causes and solving different types of cancer problems and how to limit their occurrence.…”