Saturday, October 10, 2009

Blogger's duo-editing modes allow for flexibility and convenience

In my experience using Blogger over the past several months, I have begun to appreciate more its double editing mode: Compose and Edit HTML. The Compose mode is a simple WYSIWYG editor, convenient for most common tasks. Once in a while, however, I get stuck with some nasty formatting issues that could drive one crazy to fix. This is where the Edit HTML mode comes in handy, which allows for full flexibility in editing raw HTML.

In principle, I am pretty competent with HTML and could use the Edit HTML mode directly. However, raw HTML is verbose and thus not that convenient. So I normally start a blog post with the Compose mode for most of the content, and switch to the Edit HTML mode only when necessary. Blogger makes the switch between the two modes a simple button click. This is in contrast to the single editing mode in phpBB3 (BBCode) used by the 3DNA forum, which does not allow for direct access to HTML.

Ideally, a software tool should be both flexible and convenient. In reality, however, not that many software could strike a balance between the two factors. Blogger is a nice example. Interesting, in composing this post, I switched back and forth between the two editing modes a couple of occasions: one after copy-and-pasting Edit HTML to stop red coloring of the following text, and the other to qualify the 3DNA forum link text.

Friday, October 9, 2009

Fiber models in 3DNA make it easy to build regular DNA helices

3DNA contains 55 fiber models compiled from literature. To the best of my knowledge, this is the most comprehensive collection of its kind (detailed list given below), including:
  1. Chandrasekaran & Arnott (from #1 to #43) — the most well-known set of fiber models
  2. Alexeev et al. (#44-#45)
  3. van Dam & Levitt (#46-#47)
  4. Premilat & Albiser (#48-#55)
The utility program fiber puts the generation of all these fiber models in a simple, consistent interface, and can generate structures in either standard PDB or PDBML format. Of those models, some can be built with an arbitrary sequence of A, C, G and T (e.g., A-/B-/C-DNA from calf thymus), while others are of fixed sequences (e.g., Z-DNA with GC repeats). The sequence can be specified either from command-line or a plain text file.

Once 3DNA in properly installed, the command-line interface is the most versatile and convenient way to generate, e.g., a regular double strand DNA (mostly, B-DNA) of arbitrary sequence. Moreover, the w3DNA and 3DART web-interfaces to 3DNA make it easy to generate a regular DNA model, especially for occasional use or educational purposes.

Theoretically, there is nothing to worth showing off in 3DNA's fiber model generation functionality. However, it serves as a clear example of the differences between a "proof of concept" and a practical software application. I initially decided to work on this issue simply for my own convenience. At that time, I had access to A-DNA and B-DNA fiber model generators, each as a separate program. Moreover, the constructed models did not comply to the PDB format in atom naming and other subtitles.

I started with the Chandrasekaran & Arnott fiber models which I had a copy of data files. Nevertheless, there are many details to work out, typos to correct, etc to put them in a consistent framework. For other models, I read each original publication, and typed into computer raw atomic cylindrical coordinates for each model. Again, quite a few inconsistencies popped up between the different publications with a time span over decades.

Overall, it was a quite tedious undertaking, requiring great attention to details. I am glad that I did that: I learned so much from the process, and more importantly, others can benefit from my effort. As I put in the 3DNA Nature Protocol paper (BOX 6 | FIBER-DIFFRACTION MODELS),

In preparing this set of fiber models, we have taken great care to ensure the accuracy and consistency of the models. For completeness and user verification, 3DNA includes, in addition to 3DNA-processed files, the original coordinates collected from the literature.

For those who want to understand what's going on under the hood, there is no better way than to try to reproduce the process using, e.g., fiber B-DNA as an example.

From the very beginning, I had expected the fiber functionality to be easily reachable and thus beneficial to all those who are interested in nucleic acid structures, especially to build a regular DNA duplex of chosen sequence. In my sense, the fiber program has not been widely used as it should have been, probably due to the fact that many people are not aware of its existence or capability. Hopefully, this blog post would help to get my message across.

PS. Given below is the content of the README file for fiber models in 3DNA
1. The repeating units of each fiber structure are mostly based on the
   work of Chandrasekaran & Arnott (from #1 to #43). More recent fiber
   models are based on Alexeev et al. (#44-#45), van Dam & Levitt (#46
   -#47) and Premilat & Albiser (#48-#55).

2. Clean up of each residue
   a. currently ignore hydrogen atoms [can be easily added]
   b. change ME/C7 group of thymine to C5M
   c. re-assign O3' atom to be attached with C3'
   d. change distance unit from nm to A [most of the entries]
   e. re-ordering atoms according to the NDB convention

3. Fix up of problem structures.
   a. str#8 has no N9 atom for guanine
   b. str#10 is not available from the disk, manually input
   c. str#14 C5M atom was named C5 for Thymine, resulting two C5 atoms
   d. str#17 has wrong assignment of O3' atom on Guanine
   e. str#33 has wrong C6 position in U3
   f. str#37 to #str41 were typed in manually following Arnott's
        new list as given in "Oxford Handbook of Nucleic Acid Structure"
        edited by S. Neidle (Oxford Press, 1999)
   g. str#38 coordinates for N6(A) and N3(T) are WRONG as given in the
        original literature
   h. str#39 and #40 have the same O3' coordinates for the 2nd strand

4. str#44 & 45 have fixed strand II residues (T)

5. str#46 & 47 have +z-axis upwards (based on BI.pdb & BII.pdb)

6. str#48 to 55 have +z-axis upwards

List of 55 fiber structures

id#  Twist   Rise        Structure description
    (dgrees)  (A)
 1   32.7   2.548  A-DNA  (calf thymus; generic sequence: A, C, G and T)
 2   65.5   5.095  A-DNA  poly d(ABr5U) : poly d(ABr5U)
 3    0.0  28.030  A-DNA  (calf thymus) poly d(A1T2C3G4G5A6A7T8G9G10T11) :
                                        poly d(A1C2C3A4T5T6C7C8G9A10T11)
 4   36.0   3.375  B-DNA  (calf thymus; generic sequence: A, C, G and T)
 5   72.0   6.720  B-DNA  poly d(CG) : poly d(CG)
 6  180.0  16.864  B-DNA  (calf thymus) poly d(C1C2C3C4C5) : poly d(G6G7G8G9G10)
 7   38.6   3.310  C-DNA  (calf thymus; generic sequence: A, C, G and T)
 8   40.0   3.312  C-DNA  poly d(GGT) : poly d(ACC)
 9  120.0   9.937  C-DNA  poly d(G1G2T3) : poly d(A4C5C6)
10   80.0   6.467  C-DNA  poly d(AG) : poly d(CT)
11   80.0   6.467  C-DNA  poly d(A1G2) : poly d(C3T4)
12   45.0   3.013  D-DNA  poly d(AAT) : poly d(ATT)
13   90.0   6.125  D-DNA  poly d(CI) : poly d(CI)
14  -90.0  18.500  D-DNA  poly d(A1T2A3T4A5T6) : poly d(A1T2A3T4A5T6)
15  -60.0   7.250  Z-DNA  poly d(GC) : poly d(GC)
16  -51.4   7.571  Z-DNA  poly d(As4T) : poly d(As4T)
17    0.0  10.200  L-DNA  (calf thymus) poly d(GC) : poly d(GC)
18   36.0   3.230  B'-DNA alpha poly d(A) : poly d(T) (H-DNA)
19   36.0   3.233  B'-DNA beta2 poly d(A) : poly d(T) (H-DNA  beta)
20   32.7   2.812  A-RNA  poly (A) : poly (U)
21   30.0   3.000  A'-RNA poly (I) : poly (C)
22   32.7   2.560  Hybrid poly (A) : poly d(T)
23   32.0   2.780  Hybrid poly d(G) : poly (C)
24   36.0   3.130  Hybrid poly d(I) : poly (C)
25   32.7   3.060  Hybrid poly d(A) : poly (U)
26   36.0   3.010  10-fold poly (X) : poly (X)
27   32.7   2.518  11-fold poly (X) : poly (X)
28   32.7   2.596  Poly (s2U) : poly (s2U) (symmetric base-pair)
29   32.7   2.596  Poly (s2U) : poly (s2U) (asymmetric base-pair)
30   32.7   3.160  Poly d(C) : poly d(I) : poly d(C)
31   30.0   3.260  Poly d(T) : poly d(A) : poly d(T)
32   32.7   3.040  Poly (U) : poly (A) : poly(U) (11-fold)
33   30.0   3.040  Poly (U) : poly (A) : poly(U) (12-fold)
34   30.0   3.290  Poly (I) : poly (A) : poly(I)
35   31.3   3.410  Poly (I) : poly (I) : poly(I) : poly(I)
36   60.0   3.155  Poly (C) or poly (mC) or poly (eC)
37   36.0   3.200  B'-DNA beta2  Poly d(A) : poly d(U)
38   36.0   3.240  B'-DNA beta1  Poly d(A) : poly d(T)
39   72.0   6.480  B'-DNA beta2  Poly d(AI) : poly d(CT)
40   72.0   6.460  B'-DNA beta1  Poly d(AI) : poly d(CT)
41  144.0  13.540  B'-DNA  Poly d(AATT) : poly d(AATT)
42   32.7   3.040  Poly(U) : poly d(A) : poly(U) [cf. #32]
43   36.0   3.200  Beta Poly d(A) : Poly d(U) [cf. #37]
44   36.0   3.233  Poly d(A) : poly d(T) (Ca salt)
45   36.0   3.233  Poly d(A) : poly d(T) (Na salt)
46   36.0   3.38   B-DNA (BI-type nucleotides; generic sequence: A, C, G and T)
47   40.0   3.32   C-DNA (BII-type nucleotides; generic sequence: A, C, G and T)
48   87.8   6.02   D(A)-DNA  ploy d(AT) : ploy d(AT) (right-handed)
49   60.0   7.20   S-DNA  ploy d(CG) : poly d(CG) (C_BG_A, right-handed)
50   60.0   7.20   S-DNA  ploy d(GC) : poly d(GC) (C_AG_B, right-handed)
51   31.6   3.22   B*-DNA  poly d(A) : poly d(T)
52   90.0   6.06   D(B)-DNA  poly d(AT) : poly d(AT) [cf. #48]
53  -38.7   3.29   C-DNA (generic sequence: A, C, G and T) (depreciated)
54   32.73  2.56   A-DNA (generic sequence: A, C, G and T) [cf. #1]
55   36.0   3.39   B-DNA (generic sequence: A, C, G and T) [cf. #4]
List 1-41 based on Struther Arnott: ``Polynucleotide secondary structures:
     an historical perspective'', pp. 1-38 in ``Oxford Handbook of Nucleic
     Acid Structure'' edited by Stephen Neidle (Oxford Press, 1999).
     #42 and #43 are from Chandrasekaran & Arnott: "The Structures of DNA
     and RNA Helices in Oriented Fibers", pp 31-170 in "Landolt-Bornstein
     Numerical Data and Functional Relationships in Science and Technology"
     edited by W. Saenger (Springer-Verlag, 1990).

#44-#45 based on Alexeev et al., ``The structure of poly(dA) . poly(dT)
     as revealed by an X-ray fiber diffraction''. J. Biomol. Str. Dyn, 4,
     pp. 989-1011, 1987.

#46-#47 based on van Dam & Levitt, ``BII nucleotides in the B and C forms
     of natural-sequence polymeric DNA: a new model for the C form of DNA''.
     J. Mol. Biol., 304, pp. 541-561, 2000.

#48-#55 based on Premilat & Albiser, ``A new D-DNA form of poly(dA-dT) .
     poly(dA-dT): an A-DNA type structure with reversed Hoogsteen Pairing''.
     Eur. Biophys. J., 30, pp. 404-410, 2001 (and several other publications).

Sunday, October 4, 2009

3DNA in molecular dynamics simulations

While updating 3DNA citations last Friday, I came across the paper "Flexibility of Short-Strand RNA in Aqueous Solution as Revealed by Molecular Dynamics Simulation: Are A-RNA and A′-RNA Distinct Conformational Structures?" by Ouyang et al. [Aust. J. Chem. 2009, 62, 1054–1061]. Through molecular dynamics (MD) simulations over a 30 ns period, the authors found that "the identification of distinct A-RNA and A′-RNA structures ... may not be generally relevant in the context of RNA in the aqueous phase." Overall, the paper is nicely written.

I have never performed MD simulations in my research experience, so normally I only read abstracts of such publications just to get a general idea of the main conclusions. What had attracted my attention to this work was its simultaneous citations to three earlier papers:
This is quite unusual, since nowadays it is far more common to only cite 3DNA itself (mostly 2003 NAR and/or 2008 NP). So I decided to have a look of the whole paper. It turned out that the authors used the extra citations to justify their choice of using 3DNA instead of Curves to calculate the helical parameters, including
"the three main structural descriptors commonly used to differentiate between the two forms of RNA – namely major groove width, inclination and the number of base pairs in a helical twist [turn]".

I communicated to the authors about the availability of Curves+. Specifically, using one case (413D, one of the three structures in their Table 1, "Comparison of different results by CURVES and 3DNA programs"), I've tried to illustrate the point that Curves+ and 3DNA now give directly comparable parameters.

Of course, I am glad to see 3DNA being applied to molecular dynamics simulations of nucleic acid structures.
Hopefully, more such applications will show up in the future, and I am willing to offer my help in ways that make sense to me.