A detailed understanding of the physicochemical factors that control protein-ligand binding affinities is of fundamental importance in order to address many questions in biochemistry and pharmacology, and is essential for successful execution of structure-based drug design projects. The biotin-streptavidin complex serves as an excellent model system for a high-affinity protein-ligand complex that is amenable to both detailed biophysical measurements and computational studies. Using a combination of experimental and computational methods, we have discovered and characterized several distal point mutations (I.e., point mutations far from the ligand binding site) that have no impact on equilibrium structure but that reduce biotin binding affinity dramatically. We will present results for some specific mutations, and discuss implications of these observations for protein-ligand complexes in general.

Biotin-streptavidin complex as a model system for high affinity ligand binding: Some unexpected results from biophysical and computational studies

243rd National Meeting (2012)

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