Exploring NMR ensembles of calcium binding proteins: Perspectives to design inhibitors of protein-protein interactions

<p>Abstract</p> <p>Background</p> <p>Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. However, structural changes occurring at the binding interfaces make difficult drug discovery processes using structure-based drug design/virtual screening approaches. Here we focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding.</p> <p>Results</p> <p>In order to find suitable protein conformations of calmodulin and centrin for further structure-based drug design/virtual screening, we performed <it>in silico </it>structural/energetic analysis and molecular docking of terphenyl (a mimicking alpha-helical molecule known to inhibit protein-protein interactions of calmodulin) into X-ray and NMR ensembles of calmodulin and centrin. We employed several scoring methods in order to find the best protein conformations. Our results show that docking on NMR structures of calmodulin and centrin can be very helpful to take into account conformational changes occurring at protein-protein interfaces.</p> <p>Conclusions</p> <p>NMR structures of protein-protein complexes nowadays available could efficiently be exploited for further structure-based drug design/virtual screening processes employed to design small molecule inhibitors of protein-protein interactions.</p

Long-Range Correlation in Atomic Vibration οf Chicken Lysozyme Backbone

Within this study we use methods such as spectral analysis that gives the spectral coefficient β, detrended fluctuations analysis that gives the scaling exponent α and the determination of Hurst exponent (H) to analyze the spatial series corresponding to the temperature factors of N, C-alpha, C and O atoms of 14 complexes of the chicken lysosyme. The mean values of the investigated parameters obtained for the 14 complexes are: β=1.779 ± 0.086, α=1.382 ± 0.009 and H=0.916. These values reveal long-range correlation in atomic vibrations corresponding to the chicken lysozyme backbone

Comparative molecular dynamics simulations of the caveolin CRAC motif in micelle and bilayer.

8th EBSA European Biophysics Congress, August 23rd–27th 2011, Budapest, HungaryCaveolins are essential membrane proteins found in caveolae. The caveolin scaffolding domain of caveolin-1 includes a short sequence containing a CRAC motif (V94TKYWFYR101) at its C-terminal end. To investigate the role of this motif in thecaveolin–membrane interaction at the atomic level, we performed a detailed structural and dynamics characterization ofa cav-1(V94-L102) nonapeptide encompassing this motif and including the first residue of cav-1 hydrophobic domain(L102), in dodecylphosphocholine (DPC) micelles and in DMPC/DHPC bicelles, as membrane mimics. nmR data revealed that this peptide folded as an amphipathic helix located in the polar head group region. The two tyrosine sidechains, flanked by arginine and lysine residues, are situated on one face of this helix, whereas the phenylalanine and tryptophan side-chains are located on the opposite face (Le Lan C. et al., 2010, Eur. Biophys. J., 39, 307-325). To investigate the interactions between the CRAC motif and the lipids, we performed molecular dynamics simulations in two different environment: a DPC micelle and a POPC bilayer.The results obtained are in good agreement with nmR data and the comparison between both systems provided insightinto the orientation of the CRAC motif at the membrane interface and into its interactions with lipid

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

International audienceBACKGROUND: 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