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|Abstract:||We present the physicochemical basis of binding for several active peptides from the compstatin family against the immune system protein C3. The peptide sequences are tailored to promote enhancement of the structural and physicochemical properties that contribute to binding, including consideration of the dynamic character of the protein/ligand system. The peptide sequences are designed using: (i) computational sequence selection and approximate binding affinity calculations, (ii) molecular dynamics simulations, and (iii) rational optimization [1–3]. A subset of the new peptides has been tested in ELISA inhibition assays using human serum, and produced comparable IC50 values to those of known peptides. The most promising new designs acquire an advantage in that they combine a more optimal balance between hydrophobicity, which is important for binding, and polarity, which is important for solubility, compared to the most potent known peptides. Thus, the new peptides are good candidates to become therapeutics, upon further optimization. Given the species specificity of known compstatin family peptides for primate but not for non-primate mammals, some of the new designs aim at binding to both human and rat C3. The dual specificity design was conducted using molecular dynamics simulations based on our recent atomic detail model for compstatin-human/rat binding ; however, the efficacy of the new peptides for rat C3 binding and inhibition remains to be seen in experimental assays using rat serum.|
|Citation:||López de Victoria, Aliana, Phanourios Tamamis, Ronald D. Gorham, Chris A. Kieslich, Meghan L. Bellows-Peterson, Christodoulos A. Floudas, Georgios Archontis, and Dimitrios Morikis. "Computational and Experimental Analysis of the Interactions Between C3 and Compstatin Family Peptides." Biophysical Journal 102, no. 3 (2012): 62a. doi: 10.1016/j.bpj.2011.11.371|
|Type of Material:||Conference Article|
|Journal/Proceeding Title:||Biophysical Journal|
|Version:||Final published version. Article is made available in OAR by the publisher's permission or policy.|
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