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Reference simulations of noncanonical nucleic acids with different ? variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA.

ABSTRACT: Refinement of empirical force fields for nucleic acids requires their extensive testing using as wide range of systems as possible. However, finding unambiguous reference data is not easy. In this paper, we analyze four systems which we suggest should be included in standard portfolio of molecules to test nucleic acids force fields, namely, parallel and antiparallel stranded DNA guanine quadruplex stems, RNA quadruplex stem, and Z-DNA. We highlight parameters that should be monitored to assess the force field performance. The work is primarily based on 8.4 ?s of 100-250 ns trajectories analyzed in detail followed by 9.6 ?s of additional selected back up trajectories that were monitored to verify that the results of the initial analyses are correct. Four versions of the Cornell et al. AMBER force field are tested, including an entirely new parm?(OL4) variant with ? dihedral specifically reparametrized for DNA molecules containing syn nucleotides. We test also different water models and ion conditions. While improvement for DNA quadruplexes is visible, the force fields still do not fully represent the intricate Z-DNA backbone conformation.

SUBMITTER: Krepl M

PROVIDER: S-EPMC3506181 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Reference simulations of noncanonical nucleic acids with different χ variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA.

Krepl Miroslav M Zgarbová Marie M Stadlbauer Petr P Otyepka Michal M Banáš Pavel P Koča Jaroslav J Cheatham Thomas E TE Jurečka Petr P Sponer Jiří J

Journal of chemical theory and computation 20120605 7

Refinement of empirical force fields for nucleic acids requires their extensive testing using as wide range of systems as possible. However, finding unambiguous reference data is not easy. In this paper, we analyze four systems which we suggest should be included in standard portfolio of molecules to test nucleic acids force fields, namely, parallel and antiparallel stranded DNA guanine quadruplex stems, RNA quadruplex stem, and Z-DNA. We highlight parameters that should be monitored to assess t ...[more]

PMID: 23197943

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Project description: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.

Dataset Information

Reference simulations of noncanonical nucleic acids with different ? variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA.

Publications

Reference simulations of noncanonical nucleic acids with different χ variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA.

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