18-BBSRC-NSF/BIO - Structural modeling of interactome to assess phenotypic effects of genetic variation

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This grant supports further collaboration between the groups of Prof Sternberg at Imperial College London and Prof Vakser at the University of Kansas, US. Today the sequences of genomes can be determined rapidly and from the gene sequences one obtains the sequence of proteins, which are central to biological function. Accordingly, a grand challenge for biology is to maximize the fundamental biological insights that can be obtained from determination of these protein sequences. In addition, genetic mutation often leads to minor differences in the gene sequence which result in the change of a single part of the protein sequence. These are known as single amino acid variants (SAVs). A vast amount of information on SAVs is available from a wide-range of organisms ranging from human through to bacteria. SAVs can either result in altered biological activity or may have no discernible effect. Understanding and predicting the effect of SAVs is central to many areas of biological research. Knowledge of the three-dimensional structure of proteins and their interactions with partner proteins (known as complexes) is therefore essential for understanding the mode of action of proteins and the interpretation of the effects of genetic variation. Under our previous collaboration the two groups developed the first version of a web-based resource called GWYRE (www.gwyre.org). This is a database of predicted 3D structures and complexes for biologically important organisms.The aim of the proposed research is to enhance the development of the GWYRE resource. To do this we will:(i) develop advanced methodology for high-throughput modelling of individual proteins(ii) develop high-throughput structure-based methods to predict interactions of experimentally determined and modelled proteins(iii) integrate (i) and (ii) to generate models for complexes(iv) develop enhanced computer algorithms to assess the effect of SAVs on structures and complexes(v) disseminate the GWYRE portal via publications, conference presentations, and the provision of training workshops(vi) engage in public outreach.