Atomistic Picture of Opening–Closing Dynamics of DNA Holliday Junction Obtained by Molecular Simulations

Abstract

Holliday junction (HJ) is a noncanonical four-way DNA structure with a prominent role in DNA repair, recombination, and DNA nanotechnology. By rearranging its four arms, HJ can adopt either closed or open state. With enzymes typically recognizing only a single state, acquiring detailed knowledge of the rearrangement process is an important step toward fully understanding the biological function of HJs. Here, we carried out standard all-atom molecular dynamics (MD) simulations of the spontaneous opening–closing transitions, which revealed complex conformational transitions of HJs with an involvement of previously unconsidered “half-closed” intermediates. Detailed free-energy landscapes of the transitions were obtained by sophisticated enhanced sampling simulations. Because the force field overstabilizes the closed conformation of HJs, we developed a system-specific modification which for the first time allows the observation of spontaneous opening–closing HJ transitions in unbiased MD simulations and opens the possibilities for more accurate HJ computational studies of biological processes and nanomaterials.

Site-Specific Investigation of DNA Holliday Junction Dynamics and Structure with 6-Methylisoxanthopterin, a Fluorescent Guanine Analog

“…7A). A recent report demonstrated that variations of the standard AMBER forcefields better simulate spontaneous transitions in HJ conformations [58]. Thus, in our case, the AMBER bsc1 forcefield could be over stabilizing the central region through increased stacking interactions; however, we note that we still detect extensive distortions in structure and heightened dynamics (Fig.…”

Structure and Internal Dynamics of Short RNA Duplexes Determined by a Combination of Pulsed EPR Methods and MD Simulations

“…By contrast, for RNA and DNA in canonical duplexes, all‐atom force fields such as the parm99BSC0+χ OL3 [42] (abbreviated as OL3 in this publication) and parm99BSC1, [43] respectively, already give results that are in excellent agreement with experimental data [44,45] . MD simulations with validated force fields further enable the study of highly flexible systems [46,47] …”

Accelerating Solvent Dynamics with Replica Exchange for Improved Free Energy Sampling

“…These replica exchange methods have previously been used to mitigate the effects of strong solvation; for example, PT has been used to accelerate surface dehydration during the adsorption of a protein, while HREX has been used to scale the hydrophobicity of proteins in both implicit and explicit , solvents. These methods have also been combined with metadynamics to enhance configurational sampling, although current applications primarily focus on biomacromolecules. − …”