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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
Accounting for epistatic interactions improves the functional analysis of protein structures
Angela D Wilkins1, Eric Venner, David C Marciano
1Department of Molecular and Human Genetics, CIBR Center for Computational and Integrative Biomedical Research and Program in Structural and Computational Biology & Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030 and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Bioinformatics (Oxford, England)
|September 12, 2013
Summary
Epistasis, or how mutations affect protein function based on genetic context, is strongest between nearby residues. This principle improves predicting protein functional sites by analyzing these neighbor interactions.
Area of Science:
- Protein bioinformatics
- Molecular evolution
- Structural biology
Background:
- Understanding protein sequence, structure, and function coevolution is crucial.
- Epistatic interactions, where mutation effects depend on genetic background, underlie these relationships.
- Hypothesis: Epistatic forces are strongest between structurally proximate residues, leading to smooth evolutionary importance.
Purpose of the Study:
- To investigate the role of structural smoothness in evolutionary importance.
- To develop a novel measure of evolutionary importance based on residue interactions.
- To improve functional site prediction in proteins.
Main Methods:
- Developed a new metric: pair-interaction Evolutionary Trace.
- Focused on interactions between structurally neighboring residues.
- Assessed functional site prediction accuracy and proteome-wide predictions.
Main Results:
- Smooth distribution of evolutionary importance scores between nearby residues enhances functional site prediction.
- Pair-interaction Evolutionary Trace yields greater functional site overlap.
- Achieved better structure-based proteome-wide functional predictions.
Conclusions:
- Structural smoothness of evolutionary importance is key to sequence-structure-function coevolution.
- Selective pressure is influenced by how mutations affect neighbor interactions.
- Redefining residue importance via neighbor epistatic interactions improves functional site annotation and protein function prediction.
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