Molecular Forces and Interactions
Research activity in molecular force focuses on the understanding of biomolecular forces and their role in nature such as in ligand/receptor interactions, protein folding and signal transduction. We have developed new methodologies that permit single molecules to be manipulated and the forces that hold them together to be measured. These include the contruction of a multiple-trap laser optical tweezer (LOT) and the UK's only biomembrane force probe (BFP). To complement these studies, we have also developed both the necessary theoretical understanding of the behaviour of molecules and novel computational tools to model these eperimental investigations; through collaboration with colleagues both within the University and internationally. Such measurements on single molecules have opened up new avenues to study normal and aberrant biological processes that are important therapeutic targets in biology and medicine. Our work in these areas of theory, computation, and bio-nanotechnology are exemplified by:
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Development of the theoretical understanding of molecular interactions and how nature tailors energy potentials for biological function, for example "Hidden complexity in the mechanical properties of titin" Nature 422 (2003) 446-449. Part of this work is undertaken in collaboration with Dr Clarke, Cambridge and Prof. Lindsay, Arizona
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Research in bio-nanotechnolgies, such as the UK's only biomembrance force probe (BBSRC) and experimental methodologies to measure biological systems and processes, for example "single molecule investigations of RNA dissociation" Biophys. J. 86 (2004) 3811-3821 . Part of this work is undertaken with Dr Emsley, Prof. Jensen, Prof. Lane, Imperial, Dr Clarke, Cambridge, and Prof. Evans, British Columbia
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Derivation and application of computational methodologies to predict and interpret measurements of biological processes, for example “Long time-scale simulations of proteins unfolding under force using the stochastic difference equation in length algorithm” Biophys. J. 88 (2005) 185A. Part of this work is undertaken with Prof. Elber, Cornell.
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The study of the mechanical properties of complex molecular architectures. Experimental results (which pleasingly verify our theoretical predictions) suggest routes to the manufacture of nano-scale devices with programmable and dynamic mechanical properties. See, for example, "Influence of architecture on the kinetic stability of molecular assemblies"
J. Amer. Chem. Soc. (2004) 1318-1319 .
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We are developing applications of force measurements for single molecule sensing and screening applications. Our work, in collaboration with the laboratory of Professor Gaub, Munich, on studying the changes in the mechanical properties of DNA on its interaction with various types of DNA-binding ligand is leading to new methodologies of drug screening. With our experience in studying protein unfolding we are currently extending these ideas to enable the screening of protein-binding ligands at the level of the single molecule.
Powerful computational facilities are required for our simulations, and the LBSA is intimately involved with the University's initiatives (SRIF 2 and 3) in high-performance computing. The SRIF-2 initiative resulted in 2005 in the deployment of the most powerful computing cluster within a UK University. Phil Williams of the LBSA leads the University’s SRIF-3 funded programme in High Performance Computing, aimed to maintain this lead and continue the provision of top-quality computational research facilities to the University of Nottingham.
Ultra-sensitive force measuring instrumentation is required to measure molecular interactions at the single molecule level. Within the laboratory we use three basic types of instrumentation; th eAFM, the BFP and the LOT. For biomolecular force measurement the AFM is limited in its application due to limitations in cantilever technology, feedback control and data sampling. We are working with collaborators in indutry and academia to attempt to address these shortcomings; for instance we are utilizing a new design of cantilever produced by colleagues in SUNY to attempt to measure sub-picoNewton forces with the AFM. Working with Evan Evans, British Columbia, we have constructed the only BFP outside of his laboratories and this is enabling the measurement of interactions hitherto unseen with AFM, and a recent project has culminated in the construction and commissioning of a multiple-spot LOT with the capacity to control up to nine optical traps simultaneously.
We look to continue our work on a number of exciting scientific challenges that we foresee will impact on important areas within medicine and biology. For instance, we have recently completed the most detailed protein unfolding simulation ever which, in combination with our experimental data, suggests protein-folding simulations in atomic detail. This work heralds a new paradigm for simulation of events over timescales hitherto unobtainable, and will find application in many areas of modelling, both within and outside biomolecular science.
Academic staff
Dr S Allen - Associate Professor and Reader in Molecular Biophysics
Professor SJB Tendler - Professor of Biophysical Chemistry
Professor PM Williams - Chair of Theoretical Biophysics