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Science 30 March 2007:
Vol. 315. no. 5820, pp. 1817 - 1822
DOI: 10.1126/science.1136782
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Research Articles

Computational Design of Peptides That Target Transmembrane Helices

Hang Yin,1* Joanna S. Slusky,1* Bryan W. Berger,1 Robin S. Walters,1 Gaston Vilaire,2 Rustem I. Litvinov,3 James D. Lear,1 Gregory A. Caputo,1 Joel S. Bennett,2 William F. DeGrado1,4{dagger}

A variety of methods exist for the design or selection of antibodies and other proteins that recognize the water-soluble regions of proteins; however, companion methods for targeting transmembrane (TM) regions are not available. Here, we describe a method for the computational design of peptides that target TM helices in a sequence-specific manner. To illustrate the method, peptides were designed that specifically recognize the TM helices of two closely related integrins ({alpha}IIbß3 and {alpha}vß3) in micelles, bacterial membranes, and mammalian cells. These data show that sequence-specific recognition of helices in TM proteins can be achieved through optimization of the geometric complementarity of the target-host complex.

1 Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Hematology-Oncology Division, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4 Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wdegrado{at}mail.med.upenn.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Spatial Structure of the Dimeric Transmembrane Domain of the Growth Factor Receptor ErbB2 Presumably Corresponding to the Receptor Active State.
E. V. Bocharov, K. S. Mineev, P. E. Volynsky, Y. S. Ermolyuk, E. N. Tkach, A. G. Sobol, V. V. Chupin, M. P. Kirpichnikov, R. G. Efremov, and A. S. Arseniev (2008)
J. Biol. Chem. 283, 6950-6956
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Transmembrane Domain Interactions Control Biological Functions of Neuropilin-1.
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Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions.
I. C. Dews and K. R. MacKenzie (2007)
PNAS 104, 20782-20787
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High-resolution design of a protein loop.
X. Hu, H. Wang, H. Ke, and B. Kuhlman (2007)
PNAS 104, 17668-17673
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Toward high-resolution prediction and design of transmembrane helical protein structures.
P. Barth, J. Schonbrun, and D. Baker (2007)
PNAS 104, 15682-15687
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Science. ISSN 0036-8075 (print), 1095-9203 (online)