Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session I Abstracts

Predicting Global Low Frequency Protein Motions in Allostery without Conformational Change: Application to CRP/FNR Family Transcription Factors Tom C. McLeish 1 , David Burnell 1 , Martin J. Cann 1 , Emkhe Pohl 1 , Shane A. Richards 1 , Thomas L. Rogers 2 , Philip D. Townsend 1 , Mark R. Wilson 1 . 1 Durham University, Durham, United Kingdom, 2 University of Manchester, Manchester, United Kingdom. Our objective is a foundational theory for how allostery can occur as a function of thermally- excited low frequency dynamics without a change in protein structure, together with predictive tools for protein design and modification [1-4]. We have generated coarse-grained models that describe the protein backbone motions of the homodimeric CRP/FNR family transcription factors, Catabolite Activated Protein (CAP) of Escherichia coli and GlxR of Corynebacterium glutamicum [3]. We demonstrate that binding the first molecule of cAMP ligand modulates the global normal modes resulting in negative co- operativity for binding the second cAMP ligand without a change in 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 [5]. [1] R.J. Hawkins and T.C.B. McLeish, Phys. Rev. Letts, 2004, 93, 098104 [2] R. J. Hawkins and T. C. B. McLeish, Biophys. J., 2006, 91, 2055-2062 [3] H. Toncrova and T.C.B. McLeish, Biophys. J., 2010 98, 2317-2326 [4] T. C. B. McLeish, T. L. Rodgers and M. R. Wilson, Phys. Biol. 2013 10 056004 [5] T.L. Rogers et al., PLOS-Biology, 2013 11(9): e1001651

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