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# EProM - Exploration of Protein Modifications

Daniël M. Bot, Jannes Peeters, Jan Aerts

► To cite this version:

Daniël M. Bot, Jannes Peeters, Jan Aerts. EProM - Exploration of Protein Modifications. Bio+MedVis @IEEE VIS 2022, Oct 2022, Oklahoma City, United States. hal-04007813

HAL Id: hal-04007813

https://hal.science/hal-04007813

Submitted on 28 Feb 2023

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Distributed under a Creative Commons Attribution 4.0 International License
## 2.2 3D Plot: Mol* Viewer

The second part (Figure 1.2) contains a Mol* viewer [8] showing the secondary and tertiary structures. The Mol* viewer was adapted to color residues by their number of modifications. The view automatically zooms in on the residues selected in the protein browser (Figure 1.1) and highlights these residues in green. In addition, hovering over a residue highlights it in red in all three views.

## 2.3 Detail Plot

The final view (Figure 1.3) contains a detail plot that facilitates exploring all modifications on the selected residues and residues in their 3D proximity. Residues are indicated by their amino acid's letter, emphasizing residues related to pathogenic mutations and separating non-consecutive residues by dots. The lines above the residue letters indicate whether those residues were selected (green) or in 3D-proximity to that selection (purple). The same colors are used to indicate the position of these residues in the 2D plot, making it easy to see whether active and binding sites are proximal to each other (see Figure A1). Hovering over a residue highlights it in red in all three views, and a mouse click opens a modal window that lists all observed modifications on that residue.

All modifications are represented by a circle stacked beneath the residue they were observed on. Hovering over a modification highlights all additional residues the modification can occur on (using arcs above the sequence), indicating its measurement uncertainty. In addition, hovering triggers a tree visualization showing which amino acids that modification can bind to according to UniMod [5]. The modifications can be colored interactively by selecting a combination of classification and modification name. The same combinations can be used to filter which modifications are shown.

# 3 COMPLEMENTARY CHALLENGE: REDESIGN

The 2022 Bio+MedVis Challenge also includes the secondary task of revising and improving an existing visualization (see http://biovis.net/2022/biovisChallenges-vis/). We identified several aspects that can be improved in a redesign. Most importantly, the vertical lines clutter the view without providing information and the modification's circles overlap to an extent that it reduces legibility. In addition, the absence of a color legend makes it impossible to determine what the colors mean.

Our redesign was developed with the objective to provide an intuitive overview of the possible modifications for the entire protein and per residue. We settled on a polar plot that shows all modifications as circles colored by their classification, mapping the modification name to the angle and residue position to the radius (Figure 2). The color scheme assigns a monochromatic hue to the *-translational and *-glycosylation classes. Modifications classified as “Artefact” or “Chemical derivative” were given a neutral color and positioned behind the other modifications.

The visualization supports several interactions and is combined with a stripped-down vertical version of the protein browser. Both visualizations can select a section of the protein sequence through brushing. The selected section is automatically highlighted in the protein browser. In addition, the hovered residue is indicated by a red circle in the polar plot and a red line in the protein browser. Finally, the mouse's position is observed to draw a line from the center, through the mouse, to the border of the circle, indicating the modification name of modifications along that line.

# 4 CONCLUSION

In this paper, we presented an interface for exploring protein modifications in the context of the protein structures, and demonstrated how uncertainty in a modification's exact position could be incorporated.

<figure><img src="image_3.png" /><figcaption>Figure 2: Our redesign. Modifications are shown as dots in a polar plot and colored by their classification. The red circle indicates the hovered residue's modifications, and the red line indicates the mouse position on the radial modification scale. Full version at Figure A2</figcaption></figure>

## ACKNOWLEDGMENTS

This work was supported in part by Hasselt University BOF grants ADMIRE [BOF21GP17] and [BOF21DOC19], and the Flemish Government programme "Onderzoeksprogramma Artificiële Inteligentie (AI)". JA is supported by Amador Bioscience. We thank Lennart Martens for providing the domain background.

## REFERENCES

[1] National library of medicine. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed: 2022/07/18.

[2] M. Bostock, V. Ogievetsky, and J. Heer. D³ data-driven documents. *IEEE transactions on visualization and computer graphics*, 17(12):2301–2309, 2011. doi: 10.1109/TVCG.2011.185

[3] R. Bouwmeester, R. Gabriels, N. Hulstaert, L. Martens, and S. Degroeve. Deeplc can predict retention times for peptides that carry as-yet unseen modifications. *Nat Methods*, 18(11):1363–1369, 2021. doi: 10.1038/s41592-021-01301-5

[4] T. U. Consortium. UniProt: the universal protein knowledgebase in 2021. *Nucleic Acids Research*, 49(D1):D480–D489, 11 2020. doi: 10.1093/nar/gkaa1100

[5] D. M. Creasy and J. S. Cottrell. Unimod: Protein modifications for mass spectrometry. *PROTEOMICS*, 4(6):1534–1536, 2004. doi: 10.1002/pro.200300744

[6] S. Degroeve, R. Gabriels, K. Velghe, R. Bouwmeester, N. Tichshenko, and L. Martens. ionbot: a novel, innovative and sensitive machine learning approach to lc-ms/ms peptide identification. *bioRxiv*, 2022. doi: 10.1101/2021.07.02.450686

[7] J. Jumper, R. Evans, A. Pritzel, T. Green, M. Figurnov, O. Ronneberger, K. Tunyasuvunakool, R. Bates, A. Žídek, A. Potapenko, et al. Highly accurate protein structure prediction with alphafold. *Nature*, 596(7873):583–589, 2021.

[8] D. Sehnal, S. Bittrich, M. Deshpande, R. Svobodová, K. Berka, V. Bazgier, S. Velankar, S. K. Burley, J. Koča, and A. S. Rose. Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. *Nucleic Acids Research*, 49(W1):W431–W437, 05 2021. doi: 10.1093/nar/gkab314

[9] M. Varadi, S. Anyango, M. Deshpande, S. Nair, C. Natassia, G. Yordanova, D. Yuan, O. Stroe, G. Wood, A. Laydon, A. Žídek, T. Green, K. Tunyasuvunakool, S. Petersen, J. Jumper, E. Clancy, R. Green, A. Vora, M. Lutfi, M. Figurnov, A. Cowie, N. Hobbs, P. Kohli, G. Kleywegt, E. Birney, D. Hassabis, and S. Velankar. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. *Nucleic Acids Research*, 50(D1):D439–D444, 11 2021. doi: 10.1093/nar/gkab1061
A APPENDIX - SUPPLEMENTARY FIGURES

<figure><img src="image_4.png" /><figcaption>Figure A1: Full screenshot of the main interface.</figcaption></figure>
**Protein:**

ROA1

P09651 | Human

Heterogeneous nuclear
ribonucleoprotein A1

► Function

**Modification Types:**

Filter types...

**Modifications:**

Filter modifications...

**Polar Modifications:**

<figure><img src="image_5.png" /></figure>

Exclude artifacts

<figure><img src="image_6.png" /></figure>

Filter type

<figure><img src="image_7.png" /></figure>

Filter modification

<figure><img src="image_8.png" /></figure>

Filter zoom

Primary structure ↕

50 -

100 -

150 -

200 -

250 -

300 -

350 - 350 K

K

**Modifications by prevalence and primary structure**

<figure><img src="image_9.png" /><figcaption>Figure A2: Full screenshot of the redesign.</figcaption></figure>
<figure><img src="image_10.png" /><figcaption>Figure A3: First sketches generated during the diverging phase.</figcaption></figure>
<figure><img src="image_11.png" /><figcaption>Figure A4: Pictures of the emerged designs.</figcaption></figure>
<figure><img src="image_12.png" /><figcaption>Figure A5: First sketches generated for the redesign exercise.</figcaption></figure>
<table><caption>Table A1: UniMod Modification Mismatch.</caption><thead><tr><th>Modification</th><th>Observed Sites</th><th>UniMod Sites</th><th>Not in UniMod</th></tr></thead><tbody><tr><td>Acetyl</td><td>M,Y,K,S,T,R,H,C</td><td>R,Y,H,K,T,S,C</td><td>M</td></tr><tr><td>Thiazolidine</td><td>M,Y,K,R,H,C,F,W</td><td>W,Y,H,R,K,C,F</td><td>M</td></tr><tr><td>glycidamide</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>FormylMet</td><td>R</td><td></td><td>R</td></tr><tr><td>GG</td><td>R,M,K</td><td>C,T,S,K</td><td>R,M</td></tr><tr><td>Formyl</td><td>M,T,K,S,R</td><td>T,K,S</td><td>M,R</td></tr><tr><td>Ub-amide</td><td>C</td><td></td><td>C</td></tr><tr><td>Dicarbamidomethyl</td><td>M,K,R,C,H</td><td>K,H,C,R</td><td>M</td></tr><tr><td>Delta:H(6)C(3)O(1)</td><td>M,K,R,C,H</td><td>K,H,C</td><td>M,R</td></tr><tr><td>Delta:H(8)C(6)O(1)</td><td>R,K</td><td>K</td><td>R</td></tr><tr><td>biotinAcrolein298</td><td>R,K,H</td><td>H,K,C</td><td>R</td></tr><tr><td>CarboxymethylDMAP</td><td>R,K</td><td></td><td>R,K</td></tr><tr><td>Dansyl</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Iodoacetanilide</td><td>K,R,C</td><td>K,C</td><td>R</td></tr><tr><td>Iodoacetanilide:13C(6)</td><td>K,C,R</td><td>K,C</td><td>R</td></tr><tr><td>Amidine</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Biotin:Thermo-21330</td><td>M,K,R</td><td>K</td><td>M,R</td></tr><tr><td>Biotin:Thermo-21328</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>MesitylOxide</td><td>K,R,H</td><td>K,H</td><td>R</td></tr><tr><td>Delta:H(3)C(3)O(2)</td><td>K</td><td></td><td>K</td></tr><tr><td>AccQTag</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Propionamide</td><td>M,R,K,C</td><td>C,K</td><td>M,R</td></tr><tr><td>SPITC</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>AEBS</td><td>K,Y,H,S,M,R</td><td>Y,S,K,H</td><td>M,R</td></tr><tr><td>Ethyl</td><td>K,D,E,R</td><td>E,D,K</td><td>R</td></tr><tr><td>SMA</td><td>R,K</td><td>K</td><td>R</td></tr><tr><td>Biotin</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Methyl</td><td>M,T,E,K,I,L,D,S,R,Q,N,H</td><td>E,D,L,I,R,Q,N,K,H,C,S,T</td><td>M</td></tr><tr><td>Diisopropylphosphate</td><td>K,T,S,Y,R</td><td>K,Y,T,S</td><td>R</td></tr><tr><td>Methylthio</td><td>D,R,N,C,K</td><td>K,C,N,D</td><td>R</td></tr><tr><td>Carbamidomethyl</td><td>M,Y,E,K,D,H,R,T,S,C</td><td>Y,T,S,E,D,H,K,C,U,M</td><td>R</td></tr><tr><td>Phenylisocyanate</td><td>K</td><td></td><td>K</td></tr><tr><td>Phenylisocyanate:2H(5)</td><td>K,R</td><td></td><td>K,R</td></tr><tr><td>SPITC:13C(6)</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>PyMIC</td><td>R</td><td></td><td>R</td></tr><tr><td>LG-lactam-K</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>LG-Hlactam-K</td><td>R,K</td><td>K</td><td>R</td></tr><tr><td>Diethyl</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Guanidinyl</td><td>M,K,R</td><td>K</td><td>M,R</td></tr><tr><td>Piperidine</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Sulfo-NHS-LC-LC-Biotin</td><td>R</td><td>K</td><td>R</td></tr><tr><td>Propionyl</td><td>M,K,R,S</td><td>S,T,K</td><td>M,R</td></tr><tr><td>Carboxymethyl</td><td>M,K,R,C,W</td><td>K,C,W,U</td><td>M,R</td></tr><tr><td>Succinyl</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Diethylphosphate</td><td>C,H,R,K</td><td>H,C,K,Y,T,S</td><td>R</td></tr><tr><td>Ethylphosphate</td><td>T,K,R,Y,S</td><td>K,Y,T,S</td><td>R</td></tr><tr><td>NO_SMX_SMCT</td><td>C</td><td></td><td>C</td></tr><tr><td>3sulfo</td><td>K,R</td><td></td><td>K,R</td></tr><tr><td>TNBS</td><td>R,K</td><td>K</td><td>R</td></tr><tr><td>Galactosyl</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>Ethoxyformyl</td><td>H</td><td></td><td>H</td></tr><tr><td>NHS-LC-Biotin</td><td>R</td><td>K</td><td>R</td></tr><tr><td>LG-anhydrolactam</td><td>K,R</td><td>K</td><td>R</td></tr><tr><td>LG-pyrrole</td><td>R,K</td><td>C,K</td><td>R</td></tr><tr><td>LG-anhydropyrrole</td><td>R,K</td><td>K</td><td>R</td></tr><tr><td>PEITC</td><td>K,C,R</td><td>K,C</td><td>R</td></tr><tr><td>ISD.z+2_ion</td><td>R,K</td><td></td><td>R,K</td></tr><tr><td>Hex-N-acetyl-D-glucosamine</td><td>N</td><td></td><td>N</td></tr></tbody></table>