Peptide-Polymer Conjugates as Model Systems To Explore the

Chapter 4

Downloaded by MICHIGAN STATE UNIV on February 19, 2015 | http://pubs.acs.org Publication Date (Web): September 22, 2014 | doi: 10.1021/bk-2014-1170.ch004

Peptide-Polymer Conjugates as Model Systems To Explore the Functional Space of Precision Polymers Niels ten Brummelhuis, Sebastian Wieczorek, Patrick Wilke, Thorsten Schwemmer, and Hans G. Börner* Laboratory for Organic Synthesis of Functional Systems, Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, D-12489 Berlin, Germany *E-mail: [email protected]

Oligopeptides and peptide-polymer conjugates provide an established platform for the exploration of the influence of monomer sequence on material properties. Various methods of selecting interesting amino-acid sequences are discussed, such as bioinspired selection or exploiting phage-display and combinatorial techniques. The use of these methods in finding sequences that specifically bind to surfaces or small molecules are discussed.

Introduction The properties of polymeric materials are strongly dependent on a wide variety of parameters, such as molecular weight, dispersity, chemical composition, stereochemistry and monomer sequence. Over the last two decades a number of methods have been developed to obtain a better control over the first three parameters, notably controlled free-radical polymerization techniques and ring-opening metathesis polymerization (1–6). Control over the tacticity and especially monomer sequence in synthetic polymers is still very limited, especially in chain-growth polymerizations, though a number of interesting approaches are currently being developed towards better control over these factors (7–9). It might currently not be easy to produce synthetic polymers with well-defined complex monomer sequences by chain-growth polymerizations, but this goal can readily be achieved for forced step-growth polymerizations, e.g. via solid-phase © 2014 American Chemical Society In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


synthesis (10–12). Solid-phase synthesis methods have been widely applied to the synthesis of biopolymers (nucleic acids, peptides and sugars) but can also be applied to other monomers (13–18). Though limitations still exist, polymers prepared through a step-growth polymerization can therefore be used for the creation of functional materials (for applications in coatings, drug-delivery, catalysis, etc.) but also to evaluate the influence of monomer sequence and stereochemistry on the properties of macromolecules, thereby defining relevant goals for the control of monomer sequences in fully artificial systems. The possibility of creating polymers with well-defined sequences faces us with the new challenge of selecting sequences that yield the properties required for a particular application. Nature has had millions of years to optimize the structure of biopolymers, something scientists typically do not have the patience for. Therefore, different methods of selection are needed. To some degree rational design can be used to introduce desired properties into a monomer sequence (19), but a large number of approximations and guesses are involved in this process, limiting the applicability and effectiveness. Alternatively, one can benefit from the optimization that nature has provided by replicating certain domains from proteins with desired properties. More general methods for the development of functional sequences are phage-display (20) or usage of chemically prepared libraries (21). In both of these methods oligopeptides are displayed and sorted to find those sequences with the desired properties. In this publication we will highlight the (dis)advantages of the various methods for the screening of monomer sequences. As examples of how such screening methods can be used to design functional materials, work focused on the binding of bioconjugates to inorganic surfaces (stainless steel and gadolinium oxide) and the drug molecule meta-tetra hydroxyphenyl chlorine performed in our group is compared. Some examples of the material properties that can be derived from these oligopeptides and their polymer-peptide conjugates will be discussed.

Results and Discussion Bioinspired Design of Bioconjugates Natural systems provide a great source of functional proteins/peptides for the development of functional materials (22–24). Bioinspired peptide-polymer/ protein-polymer conjugates are widely used for a broad range of applications (25), including enzyme stabilization (26–29) the self-organization of bioconjugates (30–33), or in adhesive systems, where proteins have proved to serve as excellent interfaces between organic and inorganic materials (34–36). Interesting natural adhesives are e.g. found in larval salivary glues used to affix the puparia of Drosophila, which are composed mainly of Thr-rich and highly glycosylated proteins (38). Furthermore, the sandcastle worm produces an underwater glue, in which the protein backbone is primarily composed of acidic and basic residues (35). Also, peptide sequences derived from adhesive proteins found in marine mussels (especially from mytilus edulis) are highly promising. As mussels adhere strongly to virtually any substrate under harsh conditions (high salt concentration, strong sheer conditions, etc.), their adhesive 56 In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


proteins have been extensively studied (39, 40). Figure 1a shows a simplified composition of a mussel byssus. Foot proteins mefp-3 and mefp-5 directly interact with the surface the mussel adheres to. They contain a large number of basic amino acids, e.g. arginine and lysine (41, 42). More importantly though is a high concentration of 3,4-dihydroxyphenylalanine (Dopa) residues, which are introduced in a post-translational process from natural tyrosine (see Figure 1b). Dopa has proven to be one of the key factors for the adhesion of the mussel foot and has shown very strong adherence to metal surfaces (43). Nevertheless, conjugates with only Doparesidues, especially under harsh conditions, will not lead to an effective and fast coating of desired surfaces, as adhesion kinetics are strongly dependent on the peptide backbone. Although adhesive residues are apparent throughout both mefp-3 and mefp-5, no obvious functional peptide oligomer can be extracted which is suitable for the preparation of peptide-polymer conjugates, where short peptides are desired (

Peptide-Polymer Conjugates as Model Systems To Explore the

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