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

Luciani T, Wenskovitch J, Chen K, Koes D, Travers T, Marai GE - BMC Proc (2014)

Bottom Line: 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 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science, Brown University, Box 1910, 02912 Providence, RI, US.

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.

No MeSH data available.


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.
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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.

Mentions: The researchers selected next the key residues in the 3D Viewer. This action highlights those residues in both the Trend Image Panel and the Protein Sequence Viewer, as shown in Figure 5. Using the Protein Sequence Viewer, the researchers identified which of these residues had changed in the conversion from scTIM to dTIM. For each different residue, the researchers returned to the 3D Viewer to inspect the structure of each of the residues and examine their interactions. At this stage the researchers did not use the remaining genomic data, as they were unsure of how to best use this information for the purpose of the contest. Under these circumstances, they identified and proposed two relevant mutations as the most likely candidates: Y101 (to E100) and D81 (to P80).


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

Luciani T, Wenskovitch J, Chen K, Koes D, Travers T, Marai GE - BMC Proc (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4155608&req=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.
Mentions: The researchers selected next the key residues in the 3D Viewer. This action highlights those residues in both the Trend Image Panel and the Protein Sequence Viewer, as shown in Figure 5. Using the Protein Sequence Viewer, the researchers identified which of these residues had changed in the conversion from scTIM to dTIM. For each different residue, the researchers returned to the 3D Viewer to inspect the structure of each of the residues and examine their interactions. At this stage the researchers did not use the remaining genomic data, as they were unsure of how to best use this information for the purpose of the contest. Under these circumstances, they identified and proposed two relevant mutations as the most likely candidates: Y101 (to E100) and D81 (to P80).

Bottom Line: 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 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science, Brown University, Box 1910, 02912 Providence, RI, US.

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.

No MeSH data available.