NSF Young Investigator

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9458178 Baker Little is known about how amino acid sequences specify the native states of proteins. The proposed research is a combined molecular biological and biophysical approach to this problem. Because the complexity the folding problem increases with chain length, the research is focused ont he shortest sequences known to fold into unique, stable structures without disulfide bonds. The goal is to identify the determinants of folding for two small - proteins which have similar secondary structural elements but different folding topologies. Both in vivo and in vitro selection methods will be used to identify 1) large sets of divergent sequences which adopt each folding topology 2) amino acid sequence changes which convert one topology into another. The 3-D structures adopted by particularly interesting sequences will be studied in detail using NMR and X-ray crystallography. Analysis of the resulting sequence- structure database and comparison with the sequences and structures of natural - proteins will seek to identify the sequence patterns which specify each of the two topologies. A detailed understanding of how amino acid sequence specifies tertiary structure for these particularly simple proteins should contribute to the understanding of the folding of more complex proteins. %%% Due to advances in technology and the initation of large scale DNA sequencing projects, DNA sequence information is being generated at an ever increasing rate. However, understanding the role of the newly sequenced genes is difficult from the DNA sequences alone; what one needs to know are the structures and functions of the proteins that the genes encode. The research project is directed at understanding the rules which connect amino acid sequences with protein structures for two particularly simple proteins. To the extent that the rules generalize, this knowledge should contribute to the understanding of the folding of larger and more complex proteins, and thus to th e interpretation of data generated in genome sequencing projects. ***