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Analyzing disease-associated protein structures with visual analytics.

Bromley D, Daggett V - AMIA Jt Summits Transl Sci Proc (2013)

Bottom Line: Protein function is related to protein structure, and understanding disease-associated structural changes is critical both to understanding protein-mediated illness and to developing clinical therapies.We have developed a visual analytics tool called ContactWalker that uses molecular dynamics simulations to investigate the structural and physical differences between wild type and disease-associated protein structures.We are now beginning to investigate mutations to other disease-associated proteins including the tumor suppressor protein p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical and Health Informatics, University of Washington, Seattle, WA.

ABSTRACT
Protein function is related to protein structure, and understanding disease-associated structural changes is critical both to understanding protein-mediated illness and to developing clinical therapies. We have developed a visual analytics tool called ContactWalker that uses molecular dynamics simulations to investigate the structural and physical differences between wild type and disease-associated protein structures. This tool has been used successfully to characterize the effects of the disease ataxia with vitamin E deficiency (AVED). We are now beginning to investigate mutations to other disease-associated proteins including the tumor suppressor protein p53.

No MeSH data available.


Related in: MedlinePlus

p53 residues stabilized (green) and destabilized (orange) by the Y220C mutation. (A) ContactWalker output. (B) Protein structure.
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f1-amia_tbi_2013_033: p53 residues stabilized (green) and destabilized (orange) by the Y220C mutation. (A) ContactWalker output. (B) Protein structure.

Mentions: We initially used ContactWalker to investigate ataxia with vitamin E deficiency (AVED), a neurodegenerative disease caused by mutations to the α-tocopherol transfer protein1; by analyzing differences in interatomic contacts, we characterized the mutation-associated structural differences, rationalized those findings with experiment, and offered a molecular-level explanation for the effects of the disease. We have since added additional physical analyses to ContactWalker and are now be eginning to investigate other mutant protein systems, including the tumor-suppressor protein p53. Figure 1 shows ContactWalker analysis of the p53 Y220C mutant. Figure 1A shows networks of mutation-associated disrupted contacts running through the protein. The focus box highlights the most disturbed region of the protein. This region, when mapped onto the protein structure (Fig. 1B), aligns with the location of a ligand binding pocket found experimentally to stabilize and rescue the mutant protein and to restore function2.


Analyzing disease-associated protein structures with visual analytics.

Bromley D, Daggett V - AMIA Jt Summits Transl Sci Proc (2013)

p53 residues stabilized (green) and destabilized (orange) by the Y220C mutation. (A) ContactWalker output. (B) Protein structure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814492&req=5

f1-amia_tbi_2013_033: p53 residues stabilized (green) and destabilized (orange) by the Y220C mutation. (A) ContactWalker output. (B) Protein structure.
Mentions: We initially used ContactWalker to investigate ataxia with vitamin E deficiency (AVED), a neurodegenerative disease caused by mutations to the α-tocopherol transfer protein1; by analyzing differences in interatomic contacts, we characterized the mutation-associated structural differences, rationalized those findings with experiment, and offered a molecular-level explanation for the effects of the disease. We have since added additional physical analyses to ContactWalker and are now be eginning to investigate other mutant protein systems, including the tumor-suppressor protein p53. Figure 1 shows ContactWalker analysis of the p53 Y220C mutant. Figure 1A shows networks of mutation-associated disrupted contacts running through the protein. The focus box highlights the most disturbed region of the protein. This region, when mapped onto the protein structure (Fig. 1B), aligns with the location of a ligand binding pocket found experimentally to stabilize and rescue the mutant protein and to restore function2.

Bottom Line: Protein function is related to protein structure, and understanding disease-associated structural changes is critical both to understanding protein-mediated illness and to developing clinical therapies.We have developed a visual analytics tool called ContactWalker that uses molecular dynamics simulations to investigate the structural and physical differences between wild type and disease-associated protein structures.We are now beginning to investigate mutations to other disease-associated proteins including the tumor suppressor protein p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical and Health Informatics, University of Washington, Seattle, WA.

ABSTRACT
Protein function is related to protein structure, and understanding disease-associated structural changes is critical both to understanding protein-mediated illness and to developing clinical therapies. We have developed a visual analytics tool called ContactWalker that uses molecular dynamics simulations to investigate the structural and physical differences between wild type and disease-associated protein structures. This tool has been used successfully to characterize the effects of the disease ataxia with vitamin E deficiency (AVED). We are now beginning to investigate mutations to other disease-associated proteins including the tumor suppressor protein p53.

No MeSH data available.


Related in: MedlinePlus