Saturday, January 22, 2011

Three structural biology papers in the latest issue of NAR cite 3DNA

While browsing the latest 39(2) January 2011 issue of Nucleic Acids Research (NAR), I found, to my great surprise, three papers that cite 3DNA. These papers, all under the "structural biology" section, are of interest to me from their titles and abstracts, so I downloaded the PDF versions and read through each of them.

For this blog post, #100 by incidence, it would be intriguing to look into the context to see how 3DNA is cited.

"Asymmetric DNA recognition by the OkrAI endonuclease, an isoschizomer of BamHI" by Vanamee et al. (Mount Sinai School of Medicine, and New England Biolabs):

Analysis of the stereochemical quality of the protein model and assignment of secondary structure were conducted with PROCHECK (13). DNA analysis was performed with 3DNA (14). Solvent-accessible surface areas were calculated in CNS with the algorithm of Lee and Richards employing a 1.4-Å probe(15). Figures were prepared using PyMOL ( [p713, from bottom left to middle right]

"DNA intercalation without flipping in the specific ThaI–DNA complex" by Firczuk et al. (Poland, Germany and UK):
An oligoduplex with the correct sequence in standard B-DNA geometry was generated with the program 3DNA (44), and manually adjusted to fit the highly distorted DNA in the structure. ... The programs COOT (45), REFMAC (46) and CNS (47) were used for refinement. [p747, top left]
Analysis with the 3DNA software (44) shows that the intercalation increases the rise between base pairs to about 7 Å or approximately twice its usual value (Figure 5B). Phosphorus–phosphorus (Pn–Pn+1) distances in the DNA backbone are only mildly altered (values range from 5.6 to 7.0 Å). Instead, the extra height of the two CG steps comes at the expense of the twist, which is reduced from its usual value of about 36° (360°/10) to between 10 and 15°. A view toward the major groove shows that the inner base pairs of the recognition sequence are strongly tilted (Figure 5). According to the 3DNA software (44), the first CG step has a negative tilt of about ~12°, which results in the oblique orientation of the following base pairs. The central GC step is characterized by a tilt close to 0°, reflecting the nearly parallel arrangement of the middle bases. Finally, the second CG step has a positive tilt of about 15° which restores the standard orientation of the downstream base pairs. A side view of the DNA indicates a bend at the center of the recognition sequence which is primarily due to the positive ~12° roll of the central GC step into the major groove (Table 1). The 3DNA program also indicates that the propeller twist is positive for the specifically recognized sequence, and (as expected for the standard B-DNA) negative for most of the flanking base pairs. [p749, top right]
Table 1. DNA distortion in complex with ThaI restriction endonuclease: all parameters were calculated with the 3DNA software (44). [p750, middle left]

"On the molecular basis of uracil recognition in DNA: comparative study of T-A versus U-A structure, dynamics and open base pair kinetics" by Fadda and Pomès (Ireland and Canada):
MD simulations were run with versions 3.3.3 up to 4.0.4 of the GROMACS software package (47,48).

Structural parameters were determined with the 3DNA software package (51,52). The pymol (www software package was used to generate figures. [p769, bottom right]

Established in 1974 and currently with an impact factor of 7.479, NAR has also been chosen by the Special Libraries Association as one of the top 100 most influential journals in medicine and biology over the last 100 years. The citations by the three papers in the latest issue of NAR illustrate unambiguously 3DNA's big impact in structural biology.

Wednesday, January 19, 2011

Ruby scripts for 3DNA analysis of molecular dynamics simulation trajectories

Over the years, I've been very pleased to see 3DNA's ever-increasing applications for the analysis of molecular dynamics (MD) simulation trajectories of nucleic acid structures. Among its other features, this illustrates that the command-line driven approach of 3DNA makes it easily integrable into the MD analysis pipeline (with some scripting, of course).

However, the lack of direct support of 3DNA to the ever more popular field of MD simulations has caused several obvious problems:
  • Repeated efforts – virtually every lab or even MD practitioner could come up with an ad hoc scripting solution.
  • Hinderance to 3DNA's even wider adoption – new comer to the MD field, or bench scientists interested in dynamics simulations would be scared off.
  • Known issues with existing approaches – most predominately the unnecessary repetitive run of find_pair to deduce base pairing information for each snapshot (model), which not only takes time, but more seriously some pairs could be missing due to melted out or distortion along the trajectory.
I've been following 3DNA's citations for years and I am well aware of the above issues: in addition to answering relevant questions in the 3DNA forum, I have blogged specifically on the topic a few times:
Of course, I am in a unique position to help solve the problem. Indeed, for the past couple of years, I've been thinking of writing scripts to make life easier for MD practitioners who care to use 3DNA. However, due to my lack of experience in MD simulations, constraints of "spare" time (plus laziness), and a want of suitable collaborator, I've never found the incentive to get the job done.

I finally decided to write some Ruby scripts to streamline the process of using 3DNA in MD simulations, after a recent question from Aneesh on "script for extracting data from 3DNA output file" in the 3DNA forum. After a few exchanges of views with Aneesh, and especially with Alpay's contribution of Python script and sample dataset, I've finished up two standalone yet connected Ruby scripts to analyze MD simulation trajectories with 3DNA and then extract various structural parameters. The details, including source code and test examples, are available in the 3DNA forum under "Ruby scripts for the analysis of MD simulation trajectories", in a newly created section titled "Molecular dynamics simulations".

The sample file ("sample_md0.pdb") distributed with the current v0.1 of the scripts contains 21 snapshots (models, 0..20), separated by MODEL/ENDMDL pairs. While the sample is based on a trajectory file from AMBER, any MD simulation packages, or NMR ensembles, can be similarly handled as well.

Now the ball is rolling. As time goes by, and with users' feedback, I will refine and expand the functionality of the scripts as necessary. I am confident to see more applications of 3DNA in the "dynamic" molecular simulation field.