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 VII Abstracts

Controlling Allosteric Networks in Proteins Nikolay Dokholyan . University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

We present a novel methodology for delineating allosteric pathways in proteins. We use this methodology to uncover the structural mechanisms responsible for coupling of distal sites on proteins and utilize it for allosteric modulation of proteins. We will present examples where inference of allosteric networks and its rewiring allows us to “rescue” cystic fibrosis transmembrane conductance regulator (CFTR), a protein associated with fatal genetic disease cystic fibrosis. We also use our methodology to control protein function allosterically. We design a novel protein domain that can be inserted into identified allosteric site of target protein. Using a drug that binds to our domain, we alter the function of the target protein. We successfully tested this methodology in vitro, in living cells and in zebrafish. We further demonstrate transferability of our allosteric modulation methodology to other systems and extend it to become ligh- activatable.

Intramolecular Communication Based on Time-dependent Linear Response Theories Lee-Wei Yang , Ban-Chiech Huang. National Tsing Hua University, Hsinchu, Taiwan. It has been an established idea in recent years that protein is a physiochemically connected network. Allostery, understood in this new context, is a manifestation of residue communicating to remote parts in a molecule, and hence a rising interest to identify communication pathways within such a network. In this short review, we first bring the attention to marked evidence demonstrating that site-directed mutation 19Å away from the functional site, could substantially impact the enzymatic activity of dihydrofolate reductase (DHFR) and these chemically sensitive remote sites are identified along the signal propagation pathways initiated from the catalytic center. We then outline a few new and notable approaches that characterize the pathways chemically, physically, geometrically (per inter-residue connectivity) and/or evolutionarily. Our new development using time-dependent linear response theories (LRTs) combined with normal mode analysis (NMA) and Langevin damping is introduced with clear physics providing time- resolved physical changes within molecules. Illustrative results are shown to demonstrate the capabilities of our method that assumes promising agreement with physical observables and point-mutation-caused functional changes. We close the discussion by commenting the advantageous distinctions of our method from others and its applicable future.

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