研究领域

Biological

The physics and chemistry of weak molecular interactions underpin the whole of biology. These determine the structure and stability of biological macromolecules and the strength and lifetime of interactions of these macromolecules with other cellular components. Understanding how a protein folds into a specific structure (which is only marginally stable) on a biologically relevant timescale, is still a significant challenge. Fundamental biophysical studies of the folding of proteins and of protein-protein interactions are key to understanding cellular function. We have two fundamental research areas: (1) How do proteins fold at the atomistic level and how is misfolding avoided? (2) How do changes in sequence, as the result of evolution, or brought about by mutation affect the biophysical properties of proteins? We study families of proteins using a multidisciplinary approach, to address specific questions: The folding of related proteins: By comparing the folding of a number of related proteins from large structural families we can investigate the relationship between amino acid sequence and topology and protein stability. The folding of multidomain proteins: Most proteins consist of a number of independently folding domains. How do domain:domain interactions modulate the properties of the protein? Importantly, how do larger, multidomain proteins avoid misfolding? Intrinsically disordered proteins (IDPs): A significant proportion of proteins have large disordered segments. These proteins are often involved in important important signalling pathways. IDPs fold upon binding to a target. We are developing the tools used to study globular protein folding to investigate the mechanisms of folding of IDPs.

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Evolution of oligomeric state through allosteric pathways that mimic ligand binding T Perica, Y Kondo, SP Tiwari, SH McLaughlin, KR Kemplen, X Zhang, A Steward, N Reuter, J Clarke, SA Teichmann – Science (2014) 346, 1254346 (DOI: 10.1126/science.1254346) Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein. JM Rogers, V Oleinikovas, SL Shammas, CT Wong, D De Sancho, CM Baker, J Clarke – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 15420 (DOI: 10.1073/pnas.1409122111) Allostery within a transcription coactivator is predominantly mediated through dissociation rate constants SL Shammas, AJ Travis, J Clarke – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 12055 (DOI: 10.1073/pnas.1405815111) Coupled folding and binding of the disordered protein PUMA does not require particular residual structure. JM Rogers, CT Wong, J Clarke – Journal of the American Chemical Society (2014) 136, 5197 (DOI: 10.1021/ja4125065) Mechanism of assembly of the non-covalent spectrin tetramerization domain from intrinsically disordered partners SA Hill, LG Kwa, SL Shammas, JC Lee, J Clarke – Journal of Molecular Biology (2014) 426, 21 (DOI: 10.1016/j.jmb.2013.08.027) The folding of a family of three-helix bundle proteins: spectrin R15 has a robust folding nucleus, unlike its homologous neighbours. LG Kwa, BG Wensley, CG Alexander, SJ Browning, BR Lichman, J Clarke – Journal of molecular biology (2014) 426, 1600 (DOI: 10.1016/j.jmb.2013.12.018) Remarkably fast coupled folding and binding of the intrinsically disordered transactivation domain of cMyb to CBP KIX SL Shammas, AJ Travis, J Clarke – J Phys Chem B (2013) 117, 13346 (DOI: 10.1021/jp404267e) A mechanistic model for amorphous protein aggregation of immunoglobulin-like domains. MB Borgia, AA Nickson, J Clarke, MJ Hounslow – Journal of the American Chemical Society (2013) 135, 6456 (DOI: 10.1021/ja308852b) Folding and Binding of an Intrinsically Disordered Protein: Fast, but Not 'Diffusion-Limited' JM Rogers, A Steward, J Clarke – Journal of the American Chemical Society (2013) 135, 1415 (DOI: 10.1021/ja309527h) Biophysics: Rough passage across a barrier B Schuler, J Clarke – Nature (2013) 502, 632 (DOI: 10.1038/nature12697) Take home lessons from studies of related proteins. Nickson, BG Wensley, J Clarke – Current opinion in structural biology (2013) 23, 66 (DOI: 10.1016/j.sbi.2012.11.009) Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. LG Randles, GJ Dawes, BG Wensley, A Steward, AA Nickson, J Clarke – The FEBS journal (2013) 280, 1018 (DOI: 10.1111/febs.12094) Slow, reversible, coupled folding and binding of the spectrin tetramerization domain. SL Shammas, JM Rogers, SA Hill, J Clarke – Biophys J (2012) 103, 2203 (DOI: 10.1016/j.bpj.2012.10.012) Separating the effects of internal friction and transition state energy to explain the slow, frustrated folding of spectrin domains. BG Wensley, LG Kwa, SL Shammas, JM Rogers, S Browning, Z Yang, J Clarke – Proceedings of the National Academy of Sciences of the United States of America (2012) 109, 17795 (DOI: 10.1073/pnas.1201793109) Learning from Nature to design new biomolecules J Clarke, W Schief – Current Opinion in Structural Biology (2012) 22, 395 (DOI: 10.1016/j.sbi.2012.07.001) Localizing internal friction along the reaction coordinate of protein folding by combining ensemble and single-molecule fluorescence spectroscopy A Borgia, BG Wensley, A Soranno, D Nettels, MB Borgia, A Hoffmann, SH Pfeil, EA Lipman, J Clarke, B Schuler – Nature Communications (2012) 3, 1195 (DOI: 10.1038/ncomms2204) Protein folding: Adding a nucleus to guide helix docking reduces landscape roughness BG Wensley, LG Kwa, SL Shammas, JM Rogers, J Clarke – Journal of Molecular Biology (2012) 423, 273 (DOI: 10.1016/j.jmb.2012.08.003) Staphylococcal biofilm-forming protein has a contiguous rod-like structure DT Gruszka, JA Wojdyla, RJ Bingham, JP Turkenburg, IW Manfield, A Steward, AP Leech, JA Geoghegan, TJ Foster, J Clarke, JR Potts – Proceedings of the National Academy of Sciences of the United States of America (2012) 109, E1011 (DOI: 10.1073/pnas.1119456109) Two immunoglobulin tandem proteins with a linking β-strand reveal unexpected differences in cooperativity and folding pathways A Steward, Q Chen, RI Chapman, MB Borgia, JM Rogers, A Wojtala, M Wilmanns, J Clarke – Journal of Molecular Biology (2012) 416, 137 (DOI: 10.1016/j.jmb.2011.12.012) Quantifying heterogeneity and conformational dynamics from single molecule FRET of diffusing molecules: recurrence analysis of single particles (RASP) A Hoffmann, D Nettels, J Clark, A Borgia, SE Radford, J Clarke, B Schuler – Physical chemistry chemical physics : PCCP (2011) 13, 1857 (DOI: 10.1039/c0cp01911a)