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Low‐throughput model design of protein folding inhibitors
Author(s) -
Broglia R.A.,
Tiana G.,
Sutto L.,
Provasi D.,
Perelli V.
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21275
Subject(s) - folding (dsp implementation) , protein folding , throughput , computational biology , high throughput screening , native state , protein design , chemistry , amino acid , protein stability , generality , sh3 domain , protein structure , biophysics , computer science , biochemistry , biology , proto oncogene tyrosine protein kinase src , phosphorylation , psychology , telecommunications , electrical engineering , wireless , psychotherapist , engineering
The stabilization energy of proteins in their native conformation is not distributed uniformly among all the amino acids, but is concentrated in few (short) fragments, fragments which play a key role in the folding process and in the stability of the protein. Peptides displaying the same sequence as these key fragments can compete with the formation of the most important native contacts, destabilizing the protein and thus inhibiting its biological activity. We present an essentially automatic method to individuate such peptidic inhibitors based on a low‐throughput screening of the fragments which build the target protein. The efficiency and generality of the method is tested on proteins Src‐SH3, G, CI2, and HIV‐1‐PR with the help of a simplified computational model. In each of the cases studied, we find few peptides displaying strong inhibitory properties, properties which are quite robust with respect to point mutations. The possibility of implementing the method through low‐throughput experimental screening of the target protein is discussed. Proteins 2007. © 2007 Wiley‐Liss, Inc.