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SUMMARY:Multiscale modelling and mutation approaches to thermal functional
  dynamics in proteins - Professor Tom McLeish (Durham University)
DTSTART:20140129T141500Z
DTEND:20140129T151500Z
UID:TALK49509@talks.cam.ac.uk
CONTACT:Aron Cohen
DESCRIPTION:\nWe present a foundational theory for how allostery can occur
  as a function of low frequency dynamics without a change in protein struc
 ture [1-3]. We have generated coarse-grained models that describe the prot
 ein backbone motions of the homodimeric CRP/FNR family transcription facto
 rs\, Catabolite Activated Protein (CAP) of Escherichia coli and GlxRof Cor
 ynebacterium glutamicum [3]. We demonstrate that binding the first molecul
 e of cAMP ligand modulates the global normal modes resulting in negative c
 o-operativity for binding the second cAMPligand without a change in mean s
 tructure. Crucially\, the value of the co-operativity is itself controlled
  by the interactions around a set of third allosteric “control sites” 
 (mapped for CAP in figure 1).  The theory makes key experimental predictio
 ns\, validated by analysis of variant proteins (mutating the key sites) by
  a combination of structural biology and isothermal calorimetry. A quantit
 ative description of allostery as a free energy landscape revealed a prote
 in ‘design space’ that identified the key inter- and intramolecular re
 gulatory parameters that frame CRP/FNR family allostery. Furthermore\, by 
 analyzing naturally occurring CAP variants from diverse species\, we demon
 strate an evolutionary selection pressure to conserve residues crucial for
  allosteric control. Our study therefore reveals significant features of t
 he mechanistic basis for allostery. The methodology establishes the means 
 to engineer allosteric mechanisms that are driven by low frequency dynamic
 s [4].\n \n\n*References*\n\n\n[1] R.J. Hawkins and T.C.B. McLeish\, Phys.
  Rev. Lett.\, *2004*\, 93\, 098104\n\n[2] R. J. Hawkins and T. C. B. McLei
 sh\, Biophys. J.\, *2006*\, 91\, 2055-2062\n\n[3] H. Toncrova and T.C.B. M
 cLeish\, Biophys. J.\, *2010* 98\, 2317-2326\n\n[4] T.L. Rogers et al.\, P
 LoS Biol\, *2013*\, 11\, e1001651\n
LOCATION:Department of Chemistry\, Cambridge\, Pfizer lecture theatre
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