Molecular modelling and bioinformatics
My research group has a broad interest in the application and development of computational methods covering different aspects of molecular modelling and bioinformatics. Techniques typically used in our lab are protein structure prediction by homology modelling and ab-initio modelling, ligand docking and virtual screening, molecular dynamics simulations and free energy calculations, evolutionary analysis of protein families, and a range of bioinformatics methods.
A main focus in our recent work is on understanding the molecular basis of P2X receptor activation and antagonism (in collaboration with Prof Evans’ group, University of Leicester). P2X receptors are ligand-gated cation channels activated by binding of extracellular ATP. The human genome encodes seven paralogs of the P2X receptor protein family (P2X1R-P2X7R) which form homo- and hetero-trimers. P2X receptors are involved in a variety of physiological and pathological processes, and specifically P2X7R is established as a drug target. For P2X7R we are interested in the features that determine paralog specificity of steric and allosteric antagonists, and we have developed a robust protocol for predicting binding poses of P2X7R antagonists. Another project is focused on determining conformational changes occurring in the transition between different states of P2X receptors, and we calculate structural models for the P2XR1 intracellular domain using ab-initio modelling informed by crosslinking derived distance constraints.
Other areas of work are in studying the evolution of function and binding sites in protein families by phylogenetic analysis, using ligand docking and molecular dynamics simulations to investigate kinase activation and inhibition, developing methods for the functional annotation of protein sequences, and studying alternative splicing and its effect on protein structure based on RNAseq data.
- Roberts JA, et al. (2012) 'Agonist binding evokes extensive conformational changes in the extracellular domain of the ATP-gated human P2X1 receptor ion channel.' Proc Natl Acad Sci USA, vol. 109. Pp. 4663–4667
- Schmid R, et al. (2013) 'The splicing landscape is globally reprogrammed during male meiosis.' Nucleic Acids Res, vol. 41. Pp. 10170–10184.
- Allsopp RC, et al. (2017) 'Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120.' Sci Rep, vol. 7. P. 725.