Using synthetic polypeptides to control the structure, assembly and functionality of proteins and biopolymers
Certain proteins, polypeptides or biopolymers found in brain tissues such as amyloid-beta or polyglutamine sequences in disease-mutated huntingtin protein may self-assemble and aggregate into fibrils that consist of extensive beta-pleated sheet structure. Those fibrils have strong hydrophobic cores and many highly directed hydrogen bonds between amino acids in cross beta-sheet conformations. The aggregates are associated with various diseases including Alzheimer’s disease or Prion, Huntington, and Kennedy diseases.
The aim of this project is to rationally design synthetic polypeptides that will be able on the one hand to disrupt and control the manner by which biopolymers or proteins such as polyglutamine sequences or amyloid-beta self-assemble and aggregate and on the other hand modify the chemical nature of the exposed part of assemblies. By this we hope to induce desired biological functionality, including immune response and clearance of the assemblies.
We believe that by means of systematic chemical modification and characterization of the structures and intermolecular interactions of the molecular assemblies we will be able to learn the design principles of such polypeptides. Such knowledge may lead to new biomaterials for various biomedical applications and novel treatment directions for diseases that are caused by protein or polypeptide assembly and aggregation.
This project is a unique attempt to use our knowledge gained in soft-matter physics and intermolecular interactions to understand how to control and manipulate rationally the structure and function of proteins. From entropic reasons we believe that macromolecules, rather than small molecules, have a better potential to induce such changes. Synthetic polypeptides have high flexibility of molecular design and good biocompatibility and therefore we would like to use them in this study.
In collaboration with Tim Deming (University of California, Log Angles).
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