NDLI: Chemical synthesis of TASP arrays and their application in protein design

Content Provider	Springer Nature Link
Author	Haehnel, Wolfgang
Copyright Year	2004
Abstract	A combinatorial synthesis of de novo proteins is described. The concept of template-assembled synthetic proteins (TASP) has been adapted to an orthogonal assembly of small libraries of purified peptide building blocks. It is combined with the spot synthesis of peptides which is exploited to array cyclic decapeptide templates on cellulose membranes. A cleavable linker on the cellulose allows control of the synthesis. The hydrophilic proteins are constructed by successive cleavage of orthogonal protecting groups on the template, followed by coupling of amphipathic helices in a predefined orientation and finally by incorporation of a cofactor. Libraries of peptides with variation of the amino acids expected to be close to the cofactor were coupled to the cellulose-bound template in all combinations, yielding up to 500 variants of a protein. Cofactors have been inserted either at non-covalent binding sites as heme and Cu$^{2+}$ or by covalent modification of amino acids as Ru-bipyridine or flavin. The proteins were screened by recording their UV-vis spectra directly on the solid support. The properties screened include the redox potential of heme proteins, charge transfer bands indicating the ligation of Cu-centers, enzymatic activity, and folding stability. Synthesis of the best hits as soluble variants was used for detailed characterization. Iterative improvement in a second screening cycle was efficient in finding novel copper proteins. We discuss the prospects of synthesizing proteins by extending the concept to β-sandwich proteins and construction of efficient peptide libraries with computer-supported design, as well as the possible usage of improved solid phase materials.
Starting Page	219
Ending Page	229
Page Count	11
File Format	PDF
ISSN	13811991
Journal	Molecular Diversity
Volume Number	8
Issue Number	3
e-ISSN	1573501X
Language	English
Publisher	Kluwer Academic Publishers
Publisher Date	2004-01-01
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Analytical Chemistry Organic Chemistry Polymer Sciences Pharmacy
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Medicine Drug Discovery Molecular Biology Physical and Theoretical Chemistry Information Systems Catalysis Inorganic Chemistry

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