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Advances in Bioinformatics
Volume 2011 (2011), Article ID 736593, 12 pages
Research Article

Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

1Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany
2Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany

Received 30 August 2011; Revised 7 November 2011; Accepted 23 November 2011

Academic Editor: Allegra Via

Copyright © 2011 Kristin Kassler et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4). Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120.