Rebuilding circular Z-DNA

[Di_Liu]

Hi Xiang-Jun, I think three steps are needed for creating such a Z-DNA ring or more generally, any Z-form helical structures:

(1) Obtaining a helical parameter file in a similar way as the A- or B-form helices;
(2) Creating the atoms of the bases based on the helical parameter file;
(3) Putting the other atoms of the sugar and phosphate groups based on the position of the bases' atoms (there are only two conformations corresponding to the pyrimidines and purines, respectively).

Do you prefer that I start a new thread on this topic?

Thanks!

[xiangjun]

Hi Di,

Thanks for chiming in on the topic on modeling Z-DNA structures with proper backbones. User @shr "would also look forward to Z-DNA backbones being included in DSSR modeling functionalities."

Let's continue the discussion through this thread. Your special interest in circular Z-DNA structures will also be taken into account.

In addition to splitting the topic as a new thread, I have also moved the thread under the Section on RNA structures (DSSR) from "General discussions (Q&As)". I aim to develop this feature within DSSR. As noted previously, the classic 3DNA suite of programs has been superseded by DSSR.

If you and @shr could share what you have done so far, I would very much like to see. The more concrete examples, the better.

Best regards,

Xiang-Jun

[shr]

My work focuses on molecular dynamics simulations of Z-DNA and its interactions with binding proteins. I'm particularly interested in understanding the mechanisms that stabilize Z-DNA, which is inherently less stable than B-DNA.
To explore this, I used the crystal structure of the ADAR1 protein bound to a short Z-DNA segment. Since the original segment was quite short, I wanted to extend the Z-DNA backbone. With your help, I was able to successfully simulate this extended structure. However, I encountered challenges in reproducing the specific protein–Z-DNA interactions observed in the crystal structure during my simulations. I believe this is due to multiple non-specific interactions forming between the DNA and the protein, which may mask or override the specific contacts I'm trying to study. It is not a Z-DNA remodeling problem but I am working on understanding Z-DNA stability.

In addition to Z-DNA, I also work on other non-canonical DNA structures, particularly G-quadruplexes (G4s). I’m developing a method to construct ideal G-quadruplex models from sequence data by first arranging guanine bases into tetrads, then building in the backbone and loop regions. As @Di_Liu suggested, I believe a similar model-building strategy could be applied to Z-DNA, to help generate consistent and realistic structures. What do you think about this approach or direction?

Thank you!

[Di_Liu]

I tried to make some progress on constructing a 168-bp circular Z-DNA structure. What I have achieved so far is determining the positions of the repeating units (each being a CG dimer) along the ring. Each position currently serves as a placeholder (a G:C pair; 84 in total), to be replaced by a Z-DNA dimer unit.

I'm attaching a screenshot of the current structure, as well as the corresponding PDB file. I think Xiang-Jun might be able to work his "tasks" magic to align and insert the Z-DNA dimer units into the specified positions.

If you think this direction makes sense, I’d be happy to post the detailed process of how I constructed this circle.

[xiangjun]

Hi @shr,

My work focuses on molecular dynamics simulations of Z-DNA and its interactions with binding proteins. I'm particularly interested in understanding the mechanisms that stabilize Z-DNA, which is inherently less stable than B-DNA. To explore this, I used the crystal structure of the ADAR1 protein bound to a short Z-DNA segment. Since the original segment was quite short, I wanted to extend the Z-DNA backbone. With your help, I was able to successfully simulate this extended structure.

Thanks for the background information about your work on Z-DNA structure. I am glad to hear that the extended Z-DNA structure allowed you to perform your simulations.

However, I encountered challenges in reproducing the specific protein–Z-DNA interactions observed in the crystal structure during my simulations. I believe this is due to multiple non-specific interactions forming between the DNA and the protein, which may mask or override the specific contacts I'm trying to study. It is not a Z-DNA remodeling problem but I am working on understanding Z-DNA stability.

Thank you for sharing your story. Z-DNA modeling is just the first step in understanding its role in biological processes. The other part is beyond the scope of DSSR.

In addition to Z-DNA, I also work on other non-canonical DNA structures, particularly G-quadruplexes (G4s). I’m developing a method to construct ideal G-quadruplex models from sequence data by first arranging guanine bases into tetrads, then building in the backbone and loop regions.

I am glad to hear about your work on G-quadruplexes. Actually, I have recently revised the G4 module in DSSR, fixed existing bugs, and added new features. The g4.x3dna.org website has undergone a complete overhaul, enabling users to upload their own structures for dynamic G4 analysis. Additionally, the DSSR-G4DB database is being actively updated on a weekly basis as new PDB entries are added. See the four blog posts comparing DSSR with other related analysis tools on G-quadruplexes: ASC-G4, Webba da Silva nomenclature, ElTetrado and related tools, and CIIS-GQ.

Moveover, I am also interested in modeling G-quadruplexes, taking G-tetrad as the building block. There are quite a few other threads in DSSR I'd like to pursue further in the future. I'd certainly like to hear more about your approach on modeling G-quadruplex.

As @Di_Liu suggested, I believe a similar model-building strategy could be applied to Z-DNA, to help generate consistent and realistic structures. What do you think about this approach or direction?

Yes, I believe the underlying principles can be generally applicable, including Z-DNA or right-handed A-/B-DNA. The approach in "Building extended Z-DNA structures with backbones using DSSR" is virtually the same as the one used for "create a 26 bp RNA from a 13 bp system".

Please provide more details. Working together with @Di_Liu, we should be able to come up with some interesting results.

Best regards,

Xiang-Jun


Best regards,

Xiang-Jun

[xiangjun]

Hi @Di_Liu,

I tried to make some progress on constructing a 168-bp circular Z-DNA structure. What I have achieved so far is determining the positions of the repeating units (each being a CG dimer) along the ring. Each position currently serves as a placeholder (a G:C pair; 84 in total), to be replaced by a Z-DNA dimer unit.

I'm attaching a screenshot of the current structure, as well as the corresponding PDB file. I think Xiang-Jun might be able to work his "tasks" magic to align and insert the Z-DNA dimer units into the specified positions.

Nice progress! Using DSSR, I can see clearly the 84 isolated G-C pairs along the circular structure. I will consider adding an option to "x3dna-dssr tasks" subcommand to replace these G-C pairs with GpC dinucleotide steps. Before doing that, it helps to manually replace a few of these G-C pairs with GpC steps to see how the structure looks like. These examples would also server as test cases to validate the new option.

If you think this direction makes sense, I’d be happy to post the detailed process of how I constructed this circle.

Yes, it does make sense. Please go ahead and post the details of your construction process. It may take several iterations to get the desired results. The more concrete our discussions are, the better we can understand each other.

Best regards,

Xiang-Jun

[Di_Liu]

Hi Xiang-Jun,

I manually aligned 5 dimer units onto the circle. As expected, it works. Only very minor adjustment of bond angles and lengths are required later. I'm attaching the screenshot and the pdb file.

Di

[xiangjun]

Hi Di,

This looks good. Please provide the commands used to generate the structures, for example, as I did in the blogpost on "Building extended Z-DNA structures with backbones using DSSR". Every detail counts for reproducibility.

Moreover, I would also consider the case where C-G pairs instead of G-C pairs are present in the structure. Or all 168 pairs with CGCG... sequence. I've thought about the case, and I think what we are trying to acheive fit under the general category of mutated backbones, given the atomic coordinates of base atoms. This is in contrast to the mutating bases feature currently implemented in `mutate_bases` in 3DNA and the `x3dna-dssr mutate` subcommand in DSSR.

Best regards,

Xiang-Jun

[Di_Liu]

Hi Xiang-Jun, I used UCSF Chimera to manually align the dimer units onto G-C pair. It's very difficult to describe it in words and make it reproducible, and that's why I think it would be fantastic if you can help with it by slightly adjusting the codes you already have for generating atoms from helical parameters. 

[xiangjun]

Hi Di,

Thanks for providing further details on how the structure was generated. Such contextual information is always helpful and serves as a valuable reference for the automated approach we aim to develop.

I will take a closer look at the topic and hopefully could come up something to share by next week. Ad hoc solution is easier to implement but I am keen for a systematic approach as mentioned briefly in my previous response.

Best regards,

Xiang-Jun