Question: Visualize Effect Of Snp Variant On Protein Structure
gravatar for Hanif Khalak
10.5 years ago by
Hanif Khalak1.2k
Doha, QA
Hanif Khalak1.2k wrote:

What tool(s) would enable me to visualize the effect of a particular residue change on a protein structure? Most tools merely provide a prediction of possible [deleterious] functional effect.

A couple which are useful for pre-computed coding nsSNPs are:

  • SNPs3D - easy to use; links to Cn3D-viewable pre-computed variant structures
  • StSNP - uses Modeller algorithm, and more updated list of nsSNPs; uses custom structure viewer

However, I want to visualize the residue change due to a novel variant on a structure. Even a suggested workflow in MATLAB, python (scipy+matplotlib) or similar would be useful.


ADD COMMENTlink modified 3.7 years ago by GabrielMontenegro560 • written 10.5 years ago by Hanif Khalak1.2k
gravatar for Melanie
10.5 years ago by
San Diego
Melanie630 wrote:

I actually think you need to think more about the science than the tools. There are various modeling tools out there that will produce a model of the structure with your SNP in it. However, the real question is: what are you going to do with that model? I presume that you want to understand whether or not this variation is likely to perturb the structure and/or function of your protein. In my opinion, the data behind the model is going to tell you more about that than the model itself.

My PhD project included some design of mutants to try to understand the role of specific residues in the structure/function of a class of proteins. I built models (using MODELER) of the mutants I was considering, and then I analyzed the data provided by the tool to understand whether the mutant I was considering was likely to introduce a steric clash or other strain. I combined that information with the information from phylogenetic and protein family sequence alignments (produced with CLUSTALW) to form a hypothesis about the likely impact of the mutation. And then I (or someone else in the lab) made the mutations to test the hypotheses.

In my opinion, the algorithms are good, but not really good enough to tell you for certain what the structural perturbations caused by a mutation will be. However, they can give you clues that you can include in your overall analysis.

ADD COMMENTlink written 10.5 years ago by Melanie630

Good perspective on the science of mutations - I agree you; I would still like to use tools to visualize my novel mutation to obtain visual site context and proximity to other residues

ADD REPLYlink written 10.5 years ago by Hanif Khalak1.2k

Having done pretty much exactly the same thing as Melanie during my PhD I have to concur. I used a slightly different set of tools, but generally similar approach

ADD REPLYlink written 10.5 years ago by Mndoci1.2k

Which set of tools? It would be useful if you submitted an answer with some details.. thanks!

ADD REPLYlink written 10.5 years ago by Hanif Khalak1.2k

This was well over a decade ago, so the options are different now, but in my case a combination of Modeller/WHATIF for the modeling part and CHARMM and a bunch of home grown utility scripts. In some cases, I actually did the alignments and superposition by hand. Today I'd use a structural alignment tool.

ADD REPLYlink written 10.5 years ago by Mndoci1.2k
gravatar for Khader Shameer
10.5 years ago by
Manhattan, NY
Khader Shameer18k wrote:

Have you tried PolyPhen / PolyPhen2 : ? Backgound literature is available here

I am not sure what do you mean by using (MATLAB/Python) workflow for this task, If the available tools are not able to address your problem, you may need to model (homology modelling or insilico mutation depending up on the availability of structure) the proteins with SNPs you are interested in and perform a molecular dynamics simulation over a time period to see the effect of mutation.

ADD COMMENTlink written 10.5 years ago by Khader Shameer18k

If crystal structure is available for your protein, you may use that structure and perform an insilico mutation using a web server like Eris (Journal Article) or modify the residue in Pymol and perform molecular dynamics over a time scale for both structures and compare the results.

ADD REPLYlink modified 2.2 years ago by _r_am30k • written 10.5 years ago by Khader Shameer18k

I agree - it's not clear where MATLAB/SciPy come in. If you want to analyse "novel" variants, i.e. create your own, you'll need the modelling tools outlined by Khader.

ADD REPLYlink written 10.5 years ago by Neilfws49k

Yes, I want to "creat my own" modified structure based on the variant that hasn't already been pre-computed ("novel") - I was hoping for some more details on the tools / steps that might accomplish this

ADD REPLYlink written 10.5 years ago by Hanif Khalak1.2k

BTW - I didn't include PolyPhen, SiFT, etc in my list since they don't even pre-compute the change in residue positions

ADD REPLYlink written 10.5 years ago by Hanif Khalak1.2k
gravatar for Tim
10.2 years ago by
Nijmegen, the Netherlands
Tim340 wrote:

We use Yasara in combination with some small scripts both to model and visualize point mutations in proteins, which gives images as shown here:

ADD COMMENTlink written 10.2 years ago by Tim340
gravatar for alexej.knaus
7.3 years ago by
alexej.knaus130 wrote:

Mutation Taster ( can predict very well all kinds of mutations on protein structure: indels, non-syn mutations, etc...

The tool is also integrated in an open platform for human variant analysis: . Users can register and create an account, upload their VCF files (that will be preprocessed: annotated, etc) and even filter them.

After filtering you can take a look into existing annotation (from dbSNP, HGMD, etc.) or create your own, that would help the community of users to interpret medically relecant variants. You can comment and rank annotations and thus provide your expertise to the community.

The platfom is beeing developed at the Institute for Medical Genetics and Human Genetics at the Charité in Berlin. --> or

ADD COMMENTlink written 7.3 years ago by alexej.knaus130
gravatar for GabrielMontenegro
3.7 years ago by
United Kingdom
GabrielMontenegro560 wrote:

How about the Variant Effect Predictor (VEP) from Ensembl:

From the main page:

VEP determines the effect of your variants (SNPs, insertions, deletions, CNVs or structural variants) on genes, transcripts, and protein sequence, as well as regulatory regions. Simply input the coordinates of your variants and the nucleotide changes to find out the:

genes and transcripts affected by the variants location of the variants (e.g. upstream of a transcript, in coding sequence, in non-coding RNA, in regulatory regions) consequence of your variants on the protein sequence (e.g. stop gained, missense, stop lost, frameshift) known variants that match yours, and associated minor allele frequencies from the 1000 Genomes Project SIFT and PolyPhen scores for changes to protein sequence

ADD COMMENTlink modified 2.2 years ago by _r_am30k • written 3.7 years ago by GabrielMontenegro560
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