Force-Field-Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA

Abstract

The Hoogsteen (HG) base pairing conformation, commonly observed in damaged and mutated DNA helices, facilitates DNA repair and DNA recognition. The free energy difference between HG and Watson–Crick (WC) base pairs has been computed in previous studies. However, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide a deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with the CHARMM36 force field. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and nonbonded energy analysis. The secondary structures of both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy, and the interaction energies tend to vary. The relative stability of the WC and HG conformations is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings highlight the impact that subtleties in force field models can have on accurately modeling DNA base pair dynamics and should stimulate further computational investigations into other dynamically important motions in DNA.

Deciphering the Role of Anions of Ionic Liquids in Modulating the Structure and Stability of ct-DNA in Aqueous Solutions

“…We have considered the G5–C20 in the ct -DNA that shows significant stability with respect to the relative fluctuations. These hydrogen bonding distances are of interest in studying the stability and conformational dynamics of DNA. , The distances are mostly conserved in the base pairs, and the glycosylic dihedral shows negligible change. This shows the stability of the ct -DNA in the IL medium.…”

“…The binding modes of the anions with the DNA groove is also observed from the simulation trajectories. Yet, further studies need to be performed taking longer simulation time and using different force-fields, or employing advanced sampling methods to obtain the complete information. − …”

Enhanced sampling strategies for molecular simulation of DNA

“…HG base pairs have also been observed in damaged DNA or DNA bound to a DNA repair complex, indicating the relevance of this alternative base pairing for cytotoxicity and cancer development. 27 A crystal structure of the sequence d(ATTAAT) 2 shows a double helix with all the bases in HG geometry, indicating that any AT-rich sequence may contain HG base pairs. 28 Advanced relaxation dispersion NMR experiments revealed the transient presence of HG geometries in naked duplex DNA, suggesting that a non-negligible amount of DNA exists in the HG configuration.…”

Direct monitoring of the thermodynamics and kinetics of DNA and RNA dinucleotide dehybridization from gaps and overhangs

“…Although not previously tested for dinucleotide-gap complexes or aHG base pairing, simulations with the bsc1-AMBER force field typically capture accurate relative stabilities between WCF and syn-Hoogsteen base pairing geometries. [81][82] Simulations with the DES-AMBER force field instead suggest that the WCF geometry is more stable (∆∆𝐹 𝑊𝐶𝐹−𝑎𝐻𝐺 ~ -8 kJ mol -1 ). For UUg:AA, WCF and aHG geometries have similar stabilities regardless of the employed force field (Fig.…”