Developing new methods to enable amino acid co-evolution algorithms to be applied to protein-protein interaction prediction

点击翻译按钮获取中文摘要

Proteins are molecules present in every cell that carry out essential biological processes. These molecules are essentially strings of simpler chemicals, called amino acids and these strings are able to self-assemble into a unique 3-D structure as soon as the protein is made by the cell's protein-making machinery (called ribosomes). It's this unique structure that determines the function of the protein (i.e. what is does in the cell and how it does it). By shining X-rays on crystallised proteins, scientists can determine their structure by looking at how the rays reflect off the layers of atoms that make up the crystal. However, this process can take many months or even years of effort. With hundreds of thousands of proteins for which the native structure is unknown, it is not surprising that scientists are keen to find clever shortcuts to working out the structure of proteins. We, like many other scientists have been trying to decipher the so-called protein folding "code" i.e. trying to work out the rules which govern how the protein finds its unique structure and then trying to program a computer with these rules to allow scientists to quickly "predict" what the structure of their protein of interest might be.Although the shape or "fold" of a single protein is an important piece of information, it is arguably even more useful to determine which proteins interact with a given protein of interest, and the geometry these so-called protein complexes i.e. groups of proteins which have evolved to stick together in a very specific way. Good examples of such complexes are found in many areas of biology and medicine. For example, a number of different protein complexes play a crucial role in controlling how blood clots. In general, protein-protein complexes underlie our whole understanding of how cells and organisms operate as "systems" - which is a field known as "systems biology". Unfortunately, experimentally studying the structure of a protein complex is even more difficult than studying the structure of a single protein, and so scientists have an urgent need for better computational tools to allow them to predict which proteins could interact and the likely overall shape of the complex that they form.In this project, we propose to exploit some recent breakthroughs in understanding how protein sequences evolve to allow us to deduce which pairs of proteins might interaction and the structures of the complexes that they form. In a nutshell we look for pairs of residues that appear to change in synchrony when we look at the different versions of the proteins found in different organisms i.e. we look for cases where a change in one amino acid always seem to occur when we see another amino acid changing. These linked changes are called "correlated mutations" and when we find them, we can be reasonably sure that the two amino acids have evolved to be close together in 3-D space in the final folded form of the protein. If we find enough correlated mutations, we can even go as far as predicting the complete structure of the protein and we hope as far as predicting the structure of a protein-protein complex in a similar way.