Finding Mutation Hotspot At Level Of Amino Acid By Spatial Proximity In Protein Structures

Question

[Obi Griffith]

Is anyone aware of a tool which allows one to apply the concept of "mutation hotspots" to 3D protein structures? It is common to define mutation hot spots at the DNA level where we define the hotspot as a region of DNA sequence with recurrent mutations. But what if we want to know if some mutations are "geographically" co-located in the 3D protein structure (e.g., in the same pocket) but not necessarily "sequentially" co-located. Even without pre-defined concepts of "pockets" if a protein structure is known then it should be possible to define some concept of physical distance between residues. Any suggestions?

Answer 1

[Malachi Griffith]

It looks like maybe the tool 'MuPIT' was created to help researchers address this question. From the Pubmed Abtract:

MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures.

Mutation position imaging toolbox (MuPIT) interactive is a browser-based application for single-nucleotide variants (SNVs), which automatically maps the genomic coordinates of SNVs onto the coordinates of available three-dimensional (3D) protein structures. The application is designed for interactive browser-based visualization of the putative functional relevance of SNVs by biologists who are not necessarily experts either in bioinformatics or protein structure. Users may submit batches of several thousand SNVs and review all protein structures that cover the SNVs, including available functional annotations such as binding sites, mutagenesis experiments, and common polymorphisms. Multiple SNVs may be mapped onto each structure, enabling 3D visualization of SNV clusters and their relationship to functionally annotated positions. We illustrate the utility of MuPIT interactive in rationalizing the impact of selected polymorphisms in the PharmGKB database, somatic mutations identified in the Cancer Genome Atlas study of invasive breast carcinomas, and rare variants identified in the exome sequencing project.

[r0ntu]

Actually, a new MuPIT version just got released today! Enhancements include a new algorithm to detect 3D hotspots called HotMAPS, flexible hotspot shape displays (not just a sphere!), an improved UI that allows easier switching between different PDB structures and homology models for the same gene, and an easier display of TCGA mutations from 31 tumour types and HotMAPS 3D regions identified in those tumour types.

Answer 2

[Malachi Griffith]

It looks like you can also visualize mutations for certain genes in a 3D context using CBioPortal. Enter a gene such as ESR1. The select the 'Mutations' tab. Then hit the '3D Structure' button beside the mutation diagram (loliplot) that shows the 1D location of observed mutations along the amino acid sequence. This opens a side panel that shows a 3D model for each PDB chain that is available for your protein of interest. You are also give some ability modify the 3D visualization and the way mutations are annotated on it. Very slick interface.

[Cyriac Kandoth]

Thanks! I'll pass along the kudos to the devs. We also recently released a standalone version called Mutation Mapper that allows you to use your own mutation list.

Answer 3

[Malachi Griffith]

Some additional options:

• Mutation 3D
• HotSpot3D
• HotMAPS

Answer 4

[dimkal]

I think the best way is to calculate a 'contact map' of a protein structure (PDB) and check if the residue pair of interest is within a cutoff. Perhaps a cutoff of 5-7 Angstroms is reasonable for what you're looking for. An easy tool to use is CMView, other, more sophisticated tools like Pymol, VMD can be used to write scripts to do this in batch.

Good Luck.

[Obi Griffith]

Great answer. Thanks!

Answer 5

[Matt]

ConSurf is a fairly sophisticated web tool for visualizing patterns of conservation on a protein structure. It utilizes an explicit phylogenetic model, not just an amino acid alignment.