Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC)

Abstract

Background The structure and dynamics of DNA are critically related to its function. Molecular dynamics (MD) simulations augment experiment by providing detailed information about the atomic motions. However, to date the simulations have not been long enough for convergence of the dynamics and structural properties of DNA. Methods MD simulations performed with AMBER using the ff99SB force field with the parmbsc0 modifications, including ensembles of independent simulations, were compared to long timescale MD performed with the specialized Anton MD engine on the B-DNA structure d(GCACGAACGAACGAACGC). To assess convergence, the decay of the average RMSD values over longer and longer time intervals was evaluated in addition to assessing convergence of the dynamics via the Kullback-Leibler divergence of principal component projection histograms. Results These MD simulations —including one of the longest simulations of DNA published to date at ~44 μs—surprisingly suggest that the structure and dynamics of the DNA helix, neglecting the terminal base pairs, are essentially fully converged on the ~1–5 μs timescale. Conclusions We can now reproducibly converge the structure and dynamics of B-DNA helices, omitting the terminal base pairs, on the μs time scale with both the AMBER and CHARMM C36 nucleic acid force fields. Results from independent ensembles of simulations starting from different initial conditions, when aggregated, match the results from long timescale simulations on the specialized Anton MD engine. General Significance With access to large-scale GPU resources or the specialized MD engine “Anton” it is possibly for a variety of molecular systems to reproducibly and reliably converge the conformational ensemble of sampled structures.

Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions

“…Currently, both CHARMM and AMBER force fields are known to reproduce the stable dynamics of DNA at microsecond time scale and beyond [83]. However, accurate reproduction of the experimental results on the sequence dependent DNA deformability using the available force fields still remains an unsolved problem [84] (see additional discussion on force field choice in SI).…”

Editorial preface

“…Cheatham et al [18] present very long (up to 44 μs) simulations of a double stranded 18-mer B-DNA helix in explicit solvent and find that the structure is essentially converged in~1-5 μs. Judging the quality of simulations in the end requires comparison to experimental data, and using simulations of crystals of RNA and DNA duplexes Case and coworkers [19] find that structural details that are smeared out in solution simulations are better preserved in the crystal simulations; the crystal lattice did however degrade slowly during the simulation.…”

Molecular dynamics simulation of a DNA duplex labeled with triarylmethyl spin radicals

“…The lifetime of some conformations is comparable, or even longer than the simulation time. To obtain a sufficient statistics one has to use enhanced sampling molecular dynamics methods or specialized high-performance computer systems, as discussed in the papers [30][31][32][33].…”