Modulation of protein-protein interactions by competitive small-molecule binding emerges as a promising avenue for drug discovery. Hot spots, i.e., amino acids with important contributions to the overall interaction energy, provide useful targets within these interfaces. To avoid time-consuming mutagenesis experiments, computational alanine screening has been developed for the prediction of hot spots based on existing structural information. Here we use the all-atom free-energy force field PFF02 to identify important amino acid residues in the complexes of the chemokine interleukin-8 (CXCL8) and an N-terminal peptide of its cognate receptor CXCR1, and of ERBIN, a molecular marker of the basolateral membrane in epithelial cells, in complex with the ERBIN-binding domain of tyrosin kinase ERBB2. The results of our analysis agree with available experimental functional assays, indicating that this approach is suitable for computational alanine screening and may help to identify competitive peptides as starting points for the development of inhibitors of protein-protein interactions for pharmaceutically relevant targets.
Skip Nav Destination
Article navigation
21 July 2009
Research Article|
July 20 2009
Probing hot spots on protein-protein interfaces with all-atom free-energy simulation
Irene Meliciani;
Irene Meliciani
1Forschungszentrum Karlsruhe GmbH,
Institut für Nanotechnologie
, Postfach 3640, D-76021 Karlsruhe, Germany
Search for other works by this author on:
Konstantin Klenin;
Konstantin Klenin
1Forschungszentrum Karlsruhe GmbH,
Institut für Nanotechnologie
, Postfach 3640, D-76021 Karlsruhe, Germany
Search for other works by this author on:
Timo Strunk;
Timo Strunk
1Forschungszentrum Karlsruhe GmbH,
Institut für Nanotechnologie
, Postfach 3640, D-76021 Karlsruhe, Germany
Search for other works by this author on:
Katja Schmitz;
Katja Schmitz
a)
2Institut für Organische Chemie,
Universität Karlsruhe
, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
Search for other works by this author on:
Wolfgang Wenzel
Wolfgang Wenzel
b)
1Forschungszentrum Karlsruhe GmbH,
Institut für Nanotechnologie
, Postfach 3640, D-76021 Karlsruhe, Germany
Search for other works by this author on:
a)
Electronic mail: katja.schmitz@ioc.uka.de. Tel.: +49-7247-82-3593. FAX: +49-7247-82-8744.
b)
Electronic mail: wenzel@int.fzk.de. URL: http://www.fzk.de/biostruct. Tel.: +49-7247-82-6386. FAX: +49-7247-82-6420.
J. Chem. Phys. 131, 034114 (2009)
Article history
Received:
May 07 2009
Accepted:
June 19 2009
Citation
Irene Meliciani, Konstantin Klenin, Timo Strunk, Katja Schmitz, Wolfgang Wenzel; Probing hot spots on protein-protein interfaces with all-atom free-energy simulation. J. Chem. Phys. 21 July 2009; 131 (3): 034114. https://doi.org/10.1063/1.3177008
Download citation file:
Sign in
Don't already have an account? Register
Sign In
You could not be signed in. Please check your credentials and make sure you have an active account and try again.
Sign in via your Institution
Sign in via your InstitutionPay-Per-View Access
$40.00