The utility of molecular dynamics (MD) simulations to model biomolecular structure, dynamics, and interactions has witnessed enormous advances in recent years due to the availability of optimized MD software and access to significant computational power, including GPU multicore computing engines and other specialized hardware. This has led researchers to routinely extend conformational sampling times to the microsecond level and beyond. The extended sampling time has allowed the community not only to converge conformational ensembles through complete sampling but also to discover deficiencies and overcome problems with the force fields. Accuracy of the force fields is a key component, along with sampling, toward being able to generate accurate and stable structures of biopolymers. The Amber force field for nucleic acids has been used extensively since the 1990s, and multiple artifacts have been discovered, corrected, and reassessed by different research groups. We present a direct comparison of two of the most recent and state-of-the-art Amber force field modifications, bsc1 and OL15, that focus on accurate modeling of double-stranded DNA. After extensive MD simulations with five test cases and two different water models, we conclude that both modifications are a remarkable improvement over the previous bsc0 force field. Both force field modifications show better agreement when compared to experimental structures. To ensure convergence, the Drew-Dickerson dodecamer (DDD) system was simulated using 100 independent MD simulations, each extended to at least 10 μs, and the independent MD simulations were concatenated into a single 1 ms long trajectory for each combination of force field and water model. This is significantly beyond the time scale needed to converge the conformational ensemble of the internal portions of a DNA helix absent internal base pair opening. Considering all of the simulations discussed in the current work, the MD simulations performed to assess and validate the current force fields and water models aggregate over 14 ms of simulation time. The results suggest that both the bsc1 and OL15 force fields render average structures that deviate significantly less than 1 Å from the average experimental structures. This can be compared to similar but less exhaustive simulations with the CHARMM 36 force field that aggregate to the ∼90 μs time scale and also perform well but do not produce structures as close to the DDD NMR average structures (with root-mean-square deviations of 1.3 Å) as the newer Amber force fields. On the basis of these analyses, any future research involving double-stranded DNA simulations using the Amber force fields should employ the bsc1 or OL15 modification.

Department of Medicinal Chemistry University of Utah 2000 East 30 South Skaggs 105 Salt Lake City Utah 84112 United States

Institute of Biophysics Academy of Sciences of the Czech Republic Královopolská 135 612 65 Brno Czech Republic

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University 17 Listopadu 12 771 46 Olomouc Czech Republic

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