James Kitchen PhD, Visiting Student from Warwicker Group, Manchester, UK

From 15th March with NS Group

Dr Jim Warwicker
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Work @ their Group:

Structure, function and environment of proteins
Jim Warwicker, James Kitchen etc..

The physicochemical properties of proteins figure prominently in relation to invivo activity and in vitro characterization. Walter Kauzmann’s oil drop model for protein folding (1959, Adv Protein Chem 14:1-63) describes the most basic characteristic of native structures, the relatively non-polar interior, and has seeded numerous studies of computational folding over the last 3 decades. The rapid increase in the 3D structural database, with the influence of structural genomics initiatives, is providing information across a range of organism and subcellular environments. Our work seeks correlations between 3D-based calculated properties and biological/environmental characteristics, including the following examples: organism growth temperature; subcellular organelle and subcellular pH; propensity for phosphorylation; cysteine reactivity and redox control; DNA/RNA-binding surfaces and binding paths. Many of these areas have not been studied in detail previously, and in each case we find that calculations based on 3D structure can contribute to predictions of the biological properties, adding to what are generally sequence-derived predictive models. Phosphorylation is a good example of our methodology. Sequence-based approaches have dominated prediction of phosphorylation sites. Our study of phosphorylated sites in the PDB shows that many of these ‘real sites’ are separated from ‘control’ serine, threonine and tyrosine sites that are not phosphorylated (in the same PDB sets). The basis of this distinction is simply stabilization of the negative phosphate charge by surrounding groups. The set of phosphorylated proteins in the PDB may be biased compared with the wider phosphoproteome. However, mass spectrometry is revolutionizing the experimental field, indicating that phosphorylation may be more widespread than previously thought. Our structure and comparative model-based procedures could be a useful complement to sequence-based methods in phosphorylation site bioinformatics.
Research and calculations that investigate structural correlates of biological activity have become widespread since the advent of structural biology. However, the bioinformatics contribution to functional annotation of genes depends largely on sequence-based methods. In the context of our growing ability to structurally annotate genomes, 3D structural bioinformatics algorithms such as those outlined here assume a new importance in refining and complementing the primary structure techniques.


Contributors: Jim Warwicker, Richard Greaves, Pedro Chan, James Kitchen, David Walker, Binbin Liu, Salim Bougouffa, James Magee.

BMC Structural Biology Research Article