Molecular Dynamics Simulations of the 136 Unique Tetranucleotide Sequences of DNA Oligonucleotides. I. Research Design and Results on d(CpG) Steps

Abstract

We describe herein a computationally intensive project aimed at carrying out molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences. This initiative was undertaken by an international collaborative effort involving nine research groups, the "Ascona B-DNA Consortium" (ABC). Calculations were carried out on the 136 cases imbedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All MD simulations were carried out using a well-defined protocol, the AMBER suite of programs, and the parm94 force field. Phase I of the ABC project involves a total of approximately 0.6 mus of simulation for systems containing approximately 24,000 atoms. The resulting trajectories involve 600,000 coordinate sets and represent approximately 400 gigabytes of data. In this article, the research design, details of the simulation protocol, informatics issues, and the organization of the results into a web-accessible database are described. Preliminary results from 15-ns MD trajectories are presented for the d(CpG) step in its 10 unique sequence contexts, and issues of stability and convergence, the extent of quasiergodic problems, and the possibility of long-lived conformational substates are discussed.

Electronic couplings and on-site energies for hole transfer in DNA: Systematic quantum mechanical/molecular dynamic study

“…26 The trajectory and parameter files were downloaded from the website of the Beveridge group. 27 Each of considered 15-basepair oligomers contains three tetranucleotide repeats 5Ј-G D ͑A B C D͒ 3 G-3Ј.…”

Conformations of poly{G}–poly{C} π stacks with high hole mobility

“…30 The MD simulations 29 were performed within well established protocol ͑the following parameters and options were used: T = 300 K, P = 1 atm, 2 fs integration step, parm94 force field, 31 TIP3P water molecules, 32 periodic boundary conditions, cutoff of 9 Å for nonbonded interactionos, particle-mesh Ewald algorithm 33 for treatment of electrostatic interactions͒. Detailed description of the methodology is given elsewhere.…”

“…It is known that simulations of DNA with the parm94 force field lead to undertwisted structures with remarkable negative slide values. 29 Analysis of stack conformations that exhibit very strong electronic couplings shows that ͑1͒ in several snapshots, the arrangement of the nucleobases is quite similar to that in the canonical G:C pair, while in some cases, the base pairs are remarkably distorted. Overall, we have not found any clear requirements for BP parameters.…”

Absolute versus Relative Entropy Parameter Estimation in a Coarse-Grain Model of DNA

“…Our training data set was generated from a database of MD simulations of the enhanced set of ABC [1,8,24] sequences as described in detail in [13]. The MD simulations were performed using standard conditions and protocols, and were of 50 to 100 or more nanoseconds in duration for each sequence.…”

“…Although other types of data, for example NMR data, could potentially be used, we focus on establishing methods tailored to the particular case of data coming from a finer-grain MD simulation due to both its easy availability and the continually improving state-of-the-art in the field; see, e.g.. [1,8,24,29]. In particular, by taking MD time series simulation data for a library of sequences as our starting point, we have access to changes in solvent condition, such as temperature and salt concentration and species, just by running the appropriate MD simulation of the library; albeit we must rely on the accuracy of the underlying MD simulation protocols and potentials.…”