Conservation of Interaction Patterns in Protein Families

点击翻译按钮获取中文摘要

9506278 Godzik Modeling of protein structures by computer, before it is determined experimentally, is an invaluable tool, aiding drug design, mutation studies and often structure determination itself. The main goal of this research is to improve existing tools for the modeling of protein structures by including extra information obtained from the new type of analysis of regularities in known protein structures. This whole approach can be best described as the reverse- engineering of protein structures on the computer. Protein structures will be "decomposed" into interacting fragments, and, by utilizing a library of "parts", they will be rebuilt. To gain experience as well as to measure progress during the method development, known structures will be modeled onto structures of other proteins from their structural families. Experience gained in the "rebuilding" of known structures will be used to make structural predictions for a number of real targets. %%% The main scientific trust in this research is to explore and utilize a new, interaction based, description of proteins. In such a description, a protein is seen as a collection of interactions between side chains, rather than as a set of points in space; thus, the very features responsible for the folding to a particular structure are directly used in the structure description itself. The quality of protein models obtained by homology modeling will be improved by using insights obtained through this new perspective, by focusing on side-chain interactions which remain constant with sequence changes even as protein backbone shifts and slides. The goals of this research will be achieved in two stages. In the first stage, traditional modeling techniques will be supplemented by additional information obtained from the analysis of protein families. In the second stage, a new modeling approach will be developed, where the predicted protein structure will be built inside-out, around interacting clusters of res idues, using fragments of structures from other proteins. To assist in achieving these goals, a set of necessary tools will be developed. A number of specific objectives, including building models of proteins with various levels of homology to the target, will be used to judge the progress of the research. ***