title: Binding affinities controlled by shifting conformational equilibria: opportunities and limitations.
abstract: Conformational selection is an established mechanism in molecular recognition. Despite its power to explain binding events, it is hardly used in protein/ligand design to modulate molecular recognition. Here, we explore the opportunities and limitations of design by conformational selection. Using appropriate thermodynamic cycles, our approach predicts the effects of a conformational shift on binding affinity and also allows one to disentangle the effects induced by a conformational shift from other effects influencing the binding affinity. The method is assessed and applied to explain the contribution of a conformational shift on the binding affinity of six ubiquitin mutants showing different conformational shifts in six different complexes.
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; Department of Chemistry, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address: servaas.michielssens@gmail.com.
authors.forename: Servaas
authors.initials: S
authors.lastname: Michielssens
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. Electronic address: bgroot@gwdg.de.
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. Electronic address: hgrubmu@gwdg.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D025801:Ubiquitin