The proposed studies seek to design and synthesize artificial chaperonins for the purpose of investigating the process of protein folding. Natural chaperonins promote the in vitro folding of proteins by encapsulating non-native and misfolded polypeptides and providing an isolated environment within which they may correctly fold. The development of abiological chaperonins will require synthetic systems large enough to encapsulate proteins. Nanoscopic, highly-symmetric coordination-cages that have recently been developed are uniquely suited to function as abiological chaperonins. Like many natural systems, coordination-cages are formed by the self-assembly of complementary building-blocks through a variety of non-covalent interactions. Their large hydrophobic interiors may provide an ideal environment for the binding of nonnative proteins through recognition of their hydrophobic regions. Once bound within the interior of a coordination- cage, the protein may fold properly. Initial studies will focus on synthesizing dodecahedral coordination- cages that may be reversibly assembled and disassembled upon stimulation with light in order to develop a means of releasing the protein guests. Structural modifications will then be made such that only specific sections of the coordination-cage hosts will be opened and closed, leaving a kinetic and thermodynamically stable binding pocket available for the recognition of subsequent nonnative polypeptides. As with any synthetic system, a multitude of structural modifications can be made in order to investigate the effects of size, shape, solubility, charge, etc. on the efficiency of protein folding. These studies will contribute to a deeper understanding of the factors that influence protein folding. Three sentence description of relevance to public health: In order for proteins to function properly, they must first fold into specific three-dimensional structures. This folding process is aided by natural container-like proteins called chaperonins. Synthesizing artificial chaperonins will give researchers a unique opportunity to investigate the complex protein folding process and gain a deeper understanding of this important and fundamental problem in biology.
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