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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
Modeling effects of human single nucleotide polymorphisms on protein-protein interactions
Shaolei Teng1, Thomas Madej, Anna Panchenko
1Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, USA.
Biophysical Journal
|March 18, 2009
Summary
Nonsynonymous single nucleotide polymorphisms (nsSNPs) impacting protein-protein interactions can destabilize binding energy, especially disease-associated variants. Predicting these effects solely on amino acid properties is unreliable; conservation and pH effects are crucial factors.
Area of Science:
- Computational Biology
- Structural Bioinformatics
- Molecular Dynamics
Background:
- Protein-protein interactions (PPIs) are crucial for cellular functions.
- Nonsynonymous single nucleotide polymorphisms (nsSNPs) can alter PPIs and are linked to diseases.
- Understanding nsSNP effects on PPIs is vital for disease mechanism elucidation.
Purpose of the Study:
- To investigate the impact of nsSNPs at PPI interfaces on binding energy.
- To differentiate the effects of disease-associated (OMIM) versus non-associated nsSNPs.
- To assess the predictability of nsSNP effects based on physico-chemical properties and sequence conservation.
Main Methods:
- Homology modeling to build 3D structures of 264 protein-protein complexes.
- CHARMM force field and continuum electrostatic calculations to assess binding energy changes.
- Analysis of nsSNPs from OMIM and non-OMIM databases, sequence conservation, and pKa calculations.
Main Results:
- OMIM nsSNPs were found to destabilize the electrostatic component of binding energy more than non-OMIM nsSNPs.
- Changes in binding energy were not consistently correlated with alterations in net charge, hydrophobicity, or hydrogen bond networks.
- nsSNPs at highly conserved positions showed high variance in binding energy changes, while those at nonconserved positions had less impact on average.
- Amino acid substitutions can alter protonation states, affecting pH-dependence of binding energy.
Conclusions:
- The impact of nsSNPs on PPIs is complex and cannot be solely predicted by basic physico-chemical properties of amino acids.
- Disease-associated nsSNPs have a distinct tendency to destabilize PPIs through electrostatic effects.
- Sequence conservation and pH-dependent effects play significant roles in modulating the functional consequences of nsSNPs on protein interactions.
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