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. 2014 Aug 28;8(Suppl 2 Proceedings of the 3rd Annual Symposium on Biologica):S3.
doi: 10.1186/1753-6561-8-S2-S3. eCollection 2014.

FixingTIM: interactive exploration of sequence and structural data to identify functional mutations in protein families

Timothy Luciani  1 , John Wenskovitch  2 , Koonwah Chen  3 , David Koes  4 , Timothy Travers  4 , G Elisabeta Marai  5
Affiliations

FixingTIM: interactive exploration of sequence and structural data to identify functional mutations in protein families

Timothy Luciani et al. BMC Proc. .

Abstract

Background: Knowledge of the 3D structure and functionality of proteins can lead to insight into the associated cellular processes, speed up the creation of pharmaceutical products, and develop drugs that are more effective in combating disease.

Methods: We present the design and implementation of a visual mining and analysis tool to help identify protein mutations across a family of structural models and to help discover the effect of these mutations on protein function. We integrate 3D structure and sequence information in a common visual interface; multiple linked views and a computational backbone allow comparison at the molecular and atomic levels, while a novel trend-image visual abstraction allows for the sorting and mining of large collections of sequences and of their residues.

Results: We evaluate our approach on the triosephosphate isomerase (TIM) family structural models and sequence data and show that our tool provides an effective, scalable way to navigate a family of proteins, as well as a means to inspect the structure and sequence of individual proteins.

Conclusions: The TIM application shows that our tool can assist in the navigation of families of proteins, as well as in the exploration of individual protein structures. In conjunction with domain expert knowledge, this interactive tool can help provide biophysical insight into why specific mutations affect function and potentially suggest additional modifications to the protein that could be used to rescue functionality.

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Figures

Figure 1
Figure 1
FixingTIM visual interface with four panels: a 3D view and reference information panel (1 and 2); a protein sequence viewer (3 and 4); a trend image panel for aggregating protein families (5 and 6) with two fragment paddles (5a) and a sequence paddle (5b); and a residue view for residue distribution information (7).
Figure 2
Figure 2
Client-server architecture diagram, with TIM-instantiation as an example application.
Figure 3
Figure 3
Trend image coloring scheme based on residue properties and frequence of comparison metrics.
Figure 4
Figure 4
scTIM/dTIM comparison. The two volume views show the dTIM protein backbone (right), respectively a CPK sphere representation of scTIM (left). The trend image is sorted by the number of common residues. A side-chain polarity coloring is applied, and the two vertical selection paddles are located around position 142. The two residues shown at the bottom (green underline, respectively blue underline) correspond to the two vertical paddle selections.
Figure 5
Figure 5
Two residue mutations that may restore function to the protein; residues (K)107(D) and (E)138(E). For both residues, dTIM shares the family consensus but differs from its parent, scTIM.
See this image and copyright information in PMC

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