On the absence of intrahelical DNA dynamics on the μs to ms timescale

Abstract

DNA helices display a rich tapestry of motion on both short (< 100 ns) and long (> 1 ms) timescales. However, with the exception of mismatched or damaged DNA, experimental measures indicate that motions in the 1 µs to 1 ms range are effectively absent, which is often attributed to difficulties in measuring motions in this time range. We hypothesized that these motions have not been measured because there is effectively no motion on this timescale, as this provides a means to distinguish faithful Watson-Crick base paired DNA from damaged DNA. The absence of motion on this timescale would present a “static” DNA sequence-specific structure that matches the encounter timescales of proteins, thereby facilitating recognition. Here we report long timescale (~10-44 µs) molecular dynamics simulations of a B-DNA duplex structure that addresses this hypothesis using both an “Anton” machine and large ensembles of AMBER GPU simulations.

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

“…A better fit is a logarithmic fit over the range of 40 ps to 40 ns [33]. As will become apparent later, this is actually consistent with the current MD simulation results that suggest fairly diffuse motion across the many degrees of freedom including the DNA, water and ions, with motion that rapidly decays as we average over longer and longer timescales and effectively disappears on the 1–5 μs timescale [34]. …”

“…Interestingly, although opening events are minimal beyond the first or second base pair with the AMBER force field, these transient events lead to an observed lack of complete convergence in the DNA structure at the fifth base pair. The RAC profile calculated from the CHARMM simulations shows a similar fast decay to less than 0.5 Å in the first 120–150 ns of simulation time going to less than 0.1 Å by ~ 2.3 μs [34]. Due to more significant base pair opening events and disruption of the structure of the internal helix, the converge of the dynamics occurs on a longer timescale than was observed in the AMBER simulations, and also with a higher final RMS value of ~0.6 Å [34].…”

“…Compared to Watson-Crick DNA helices that do not show exchange processes or internal dynamics on this timescale, the NMR results of the mismatch clearly resolve exchange processes on the 26 ± 8 μs timescale, which is consistent with the higher expected opening rates. However, before jumping into the simulation results and a more elaborate discussion of the implications of a 1 μs – 1 ms gap in DNA helix dynamics [34], it is worthwhile to review progress to date and note that previously, due to limits in computational power, MD simulations were effectively limited to the sub-microsecond range.…”

Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics

“…MD can access the atomic detail of an NA structure (22)(23)(24)(25) and provide information about the mechanical response of the chain as a whole (19,23,(26)(27)(28)(29). One common approach to address this problem is to determine the elastic parameters of a given NA chain through thermal fluctuations at the equilibrium of an unrestrained sequence (19,30,31).…”

Multiscale simulation of DNA

“…The idea that B-DNA is polymorphic and that different states can coexist in its equilibrium ensemble has been widely explored in the last years by different authors [30,33,[58][59][60][61][62][63], putting special emphasis on the base fraying [59][60][61][62][63], due to its role in DNA recognition, repair, and strand slippage. The impact of DNA polymorphism in DNA allosterism [64] has been also the subject of the work of several groups [62,65], while others centered their efforts in understanding the origin of DNA curvature [66].…”