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Nature Chemical Biology
May, 2010

     

 

     

The physical basis for high affinity interactions involving proteins is complex and potentially involves a range of energetic contributions. Among these are changes in protein conformational entropy, which cannot yet be reliably computed from molecular structures. We have recently employed changes in conformational dynamics as a proxy for changes in conformational entropy of calmodulin upon association with domains from regulated proteins. The apparent change in conformational entropy was linearly related to the overall binding entropy. This view warranted a more quantitative foundation. Here we calibrate the “entropy meter” employing an experimental dynamical proxy based on NMR relaxation and show that changes in the conformational entropy of calmodulin are a significant component of the energetics of binding. Furthermore, the distribution of motion at the interface between the target domain and calmodulin are surprisingly non-complementary. These observations promote modification of our understanding of the energetics of protein-ligand interactions. This result opens the door to a broader examination of the role of conformational entropy in a range of protein-based phenomena.

Michael S. Marlow, Jakob Dogan, Kendra K. Frederick, Kathleen G. Valentine, and A. Joshua Wand (2010) The role of conformational entropy in molecular recognition by calmodulin. Nature Chemical Biology 6:352-358 (2010)