Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Convergence and reproducibility of the DNA duplex d(GCACGAACGAACGAACGC) using molecular dynamics simulations
DNA dynamics and structure are tightly related to its function. To fully understand the biological relevance, regulation and function of DNA in processes ranging from replication to transcription and repair to the interaction with transcription factors and proteins, it is important to gain atomic level insight into the sequence specific mobility, dynamics and deformability of DNA (Baranello et al.2012; Lavelle 2014). Extensive testing of the 36 possible tetra nucleotide combinations have been performed by the ABC consortium (Beveridge et al. 2004; Pasi et al. 2014; Lavery et al. 2009). Even with extensive simulation time as far as 1 µs, longer timescales are required to fully relax the BI/BII populations, bimodal twist distributions at CpG steps and ion distributions. We present the results of, to our knowledge, the longest full atom molecular dynamics simulations of the 36-mer d(CGACGAACGAACGAACGC) using the AMBER MD package and the parm99+bsc0 force field. The simulations were performed in the Anton supercomputer available in PSC for 44 µs. Additionally, the simulations were also performed using CPU and GPU hardware to ensure that these differences could not affect the outcome of MD simulations. We also include simulations of the same system using the CHARMM all36 (C36) force field (Hart et al. 2012). Overall, the results suggest that we are able to converge the internal DNA helical structure in the ∼1-5 µs time scale as determined by two independent measures of convergence: an assessment of the convergence of internal motions by overlap of principal component projection histograms as a function of time and a novel measure of overall structural convergence which we term RMS average correlation (Roe and Cheatham 3rd, 2013).
Computer time is acknowledged from NSF XSEDE Allocation MCA01S027, XSEDE/GeorgiaTech KIDS and Keeneland systems, NSF/NCSA/U Illinois Blue Waters Petascale Resource (PRAC OCI-1036208, OCI 0725070, and ACI-1238993), Anton computer time was provided by the National Center for Multiscale Modeling of Biological Systems (MMBioS, P41GM103712-S1) from the NIH and the Pittsburgh Supercomputing Center (PSC12038P, PSCA00033P). The Anton machine at PSC was generously made available by D. E. Shaw Research
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Hart, Katarina et al. Optimization of the CHARMM Additive Force Field for DNA: Improved Treatment of the BI/BII Conformational Equilibrium Journal of Chemical Theory and Computation 8.1 (2012): 348-362. Web. 27 Feb. 2013.
Lavelle, Christophe,Pack, Unpack, Bend, Twist, Pull, Push: The Physical Side of Gene Expression. Current opinion in genetics & development 25C (2014): 74-84. Web. 1 Apr. 2014.
Lavery, R. et al. A Systematic Molecular Dynamics Study of Nearest-Neighbor Effects on Base Pair and Base Pair Step Conformations and Fluctuations in B-DNA. Nucleic Acids Research 38.1 (2009): 299-313. Web. 27 Feb. 2013.
Pasi, Marco et al. µABC: A Systematic Microsecond Molecular Dynamics Study of Tetranucleotide Sequence Effects in B-DNA. Nucleic acids research 42.19 (2014): 12272-83. Web. 18 Feb. 2015.
Roe, D. R., and Thomas. E. Cheatham 3rd. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. Journal of Chemical Theory and Computation 9.7 (2013): 3084-3095. Web. 18 June 2013.
Department of Medicinal Chemistry