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SUMMARY:Dynamics and thermodynamics of ligand binding to galectin-3 - Prof
 essor Mikael Akke\, Lund University
DTSTART:20170426T093000Z
DTEND:20170426T103000Z
UID:TALK72322@talks.cam.ac.uk
CONTACT:23027
DESCRIPTION:Protein conformational dynamics can be critical for ligand bin
 ding in two ways that relate to kinetics and thermodynamics respectively. 
 First\, conformational transitions between different substates can control
  access to the binding site (kinetics). Secondly\, differences between fre
 e and ligand-bound states in their conformational fluctuations contribute 
 to the entropy of ligand binding (thermodynamics). In my talk I will summa
 rize our results on the role of conformational dynamics in ligand binding 
 to the carbohydrate-recognition domain of galectin-3. NMR relaxation exper
 iments uniquely probe conformational entropy by characterizing bond-vector
  fluctuations at atomic resolution. By monitoring differences between the 
 free and ligand-bound states in their backbone and side chain order parame
 ters\, we have estimated the contributions from conformational entropy to 
 the free energy of binding. Overall\, the conformational entropy of Gal3C 
 increases upon ligand binding\, thereby contributing favourably to the bin
 ding affinity. Comparisons with the results from isothermal titration calo
 rimetry indicate that the conformational entropy is comparable in magnitud
 e to the enthalpy of binding. Furthermore\, there are significant differen
 ces in the dynamic response to binding of different ligands\, despite the 
 fact that the protein structure is virtually identical in the different pr
 otein–ligand complexes. Thus both affinity and specificity of ligand bin
 ding to Gal3C appear to depend in part on subtle differences in the confor
 mational fluctuations that reflect the complex interplay between structure
 \, dynamics and ligand interactions. We have also studied the kinetics of 
 ligand binding using CPMG relaxation dispersion experiments. By monitoring
  the on- and off-rates of binding for a series of related compounds\, we r
 esolve linear free energy relationships that reveal the relative stabiliza
 tion of the bound state and transition state\, as well as the position of 
 the transition state along the reaction coordinate. Experiments conducted 
 with variable ligand concentration provide information on the relative imp
 ortance of (or relative flux through) the so-called induced fit and confor
 mational selection pathways of ligand binding. 
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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