Abstract
We present a foundational theory for how allostery can occur as a function of low frequency dynamics without a change in protein structure. Elastic inhomogeneities allow entropic ‘signalling at a distance’. Remarkably, many globular proteins display just this class of elastic structure, in particular those that support allosteric binding of substrates (long-range co-operative effects between the binding sites of small molecules). Through multi-scale modelling of global normal modes we demonstrate negative co-operativity between the two cAMP ligands without change to the mean structure. Crucially, the value of the co-operativity is itself controlled by the interactions around a set of third allosteric ‘control sites’. The theory makes key experimental predictions, validated by analysis of variant proteins by a combination of structural biology and isothermal calorimetry. A quantitative description of allostery as a free energy landscape revealed a protein ‘design space’ that identified the key inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, by analyzing naturally occurring CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. The methodology establishes the means to engineer allosteric mechanisms that are driven by low frequency dynamics.
Biography
Tom McLeish is Professor of Physics at Durham University. Tom did a first degree in physics and PhD (1987) in polymer physics at Cambridge University. A lectureship at Sheffield University in complex fluid physics was followed by a chair at Leeds University from 1993. He has since won several awards both in Europe (Weissenberg Medal) and the USA (Bingham Medal) for his work on molecular rheology of polymers, and ran a large collaborative and multidisciplinary research programme in this field from 1999-2009 co-funded by EPSRC and industry.
His research interests include: (i) molecular rheology of polymeric fluids); (ii) macromolecular biological physics; (iii) issues of theology, ethics and history (especially medieval) of science. He has published over 180 scientific papers and reviews, and is in addition regularly involved in science-communication with the public, including lectures and workshops on science and faith. In 2014 OUP published his book Faith and Wisdom in Science. He has been a Reader (lay preacher) in the Anglican Church since 1993, in the dioceses of Ripon and York.
From 2008-2014 he served as Pro-Vice-Chancellor for Research at Durham University. In 2011 he was elected a Fellow of the Royal Society. He served as Vice-President of Science and Innovation in the Institute of Physics 2012-2015, and is currently chair of the Royal Society’s Education Committee.
About IMSE
The Institute for Molecular Science and Engineering (IMSE) is one of Imperial College London’s Global Institutes, drawing on the strength of its four faculties to address some of the grand challenges facing the world today. The Institute’s activities are focused on tackling problems where molecular innovation plays an important role.
The Highlight Seminar Series brings eminent speakers from across the globe to Imperial to increase awareness of areas where molecular science and engineering can make a valuable contribution and to promote exchanges with academic and industrial centres of excellence.