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Open Access Research article

Computational analysis of protein-protein interfaces involving an alpha helix: insights for terphenyl–like molecules binding

Adriana Isvoran12, Dana Craciun3, Virginie Martiny45, Olivier Sperandio45 and Maria A Miteva45*

Author Affiliations

1 Department of Biology and Chemistry, West University of Timisoara, 16 Pestalozzi, Timisoara 300115, Romania

2 Advanced Environmental Researches Laboratory, 4 Oituz, Timisoara 300086, Romania

3 Teacher Training Department, West University of Timisoara, 4 Blvd. V. Parvan, Timisoara 300223, Romania

4 Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, Inserm UMR-S 973, 35 rue Helene Brion, Paris 75013, France

5 INSERM, U973, Paris F-75205, France

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BMC Pharmacology and Toxicology 2013, 14:31  doi:10.1186/2050-6511-14-31

Published: 14 June 2013

Abstract

Background

Protein-Protein Interactions (PPIs) are key for many cellular processes. The characterization of PPI interfaces and the prediction of putative ligand binding sites and hot spot residues are essential to design efficient small-molecule modulators of PPI. Terphenyl and its derivatives are small organic molecules known to mimic one face of protein-binding alpha-helical peptides. In this work we focus on several PPIs mediated by alpha-helical peptides.

Method

We performed computational sequence- and structure-based analyses in order to evaluate several key physicochemical and surface properties of proteins known to interact with alpha-helical peptides and/or terphenyl and its derivatives.

Results

Sequence-based analysis revealed low sequence identity between some of the analyzed proteins binding alpha-helical peptides. Structure-based analysis was performed to calculate the volume, the fractal dimension roughness and the hydrophobicity of the binding regions. Besides the overall hydrophobic character of the binding pockets, some specificities were detected. We showed that the hydrophobicity is not uniformly distributed in different alpha-helix binding pockets that can help to identify key hydrophobic hot spots.

Conclusions

The presence of hydrophobic cavities at the protein surface with a more complex shape than the entire protein surface seems to be an important property related to the ability of proteins to bind alpha-helical peptides and low molecular weight mimetics. Characterization of similarities and specificities of PPI binding sites can be helpful for further development of small molecules targeting alpha-helix binding proteins.