NSF Young Investigator

9458178 Baker关于氨基酸序列如何指定蛋白质的天然状态知之甚少。 拟议的研究是结合分子生物学和生物物理学的方法来解决这个问题。 由于折叠问题的复杂性随着链长的增加而增加，因此研究集中在已知折叠成独特、稳定结构而没有二硫键的最短序列上。 目标是确定两种具有相似二级结构元件但折叠拓扑结构不同的小蛋白质折叠的决定因素。 体内和体外选择方法都将用于鉴定1）采用每个折叠拓扑结构的大量不同序列，2）将一种拓扑结构转化为另一种拓扑结构的氨基酸序列变化。特别有趣的序列所采用的三维结构将使用NMR和X射线晶体学进行详细研究。 分析所得到的序列结构数据库，并与天然蛋白质的序列和结构进行比较，将试图确定指定两种拓扑结构中的每一种的序列模式。 详细了解氨基酸序列如何指定这些特别简单的蛋白质的三级结构，将有助于理解更复杂的蛋白质的折叠。 由于技术的进步和大规模DNA测序项目的启动，DNA序列信息正在以不断增长的速度产生。 然而，仅仅从DNA序列来理解新测序基因的作用是困难的;人们需要知道的是基因编码的蛋白质的结构和功能。 该研究项目旨在了解两种特别简单的蛋白质的氨基酸序列与蛋白质结构之间的联系规则。 就规则的普遍性而言，这些知识应该有助于理解更大和更复杂的蛋白质的折叠，从而有助于解释基因组测序项目中产生的数据。 ***

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. ***