Unexpected dynamics in femtomolar complexes of binding proteins with peptides

Stefano Cucuzza, Malgorzata Sitnik, Simon Jurt, Erich Michel, Wenzhao Dai, Thomas Müntener, Patrick Ernst, Daniel Häussinger, Andreas Plückthun () and Oliver Zerbe ()
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Stefano Cucuzza: University of Zürich, Winterthurerstrasse
Malgorzata Sitnik: University of Zürich, Winterthurerstrasse
Simon Jurt: University of Zürich, Winterthurerstrasse
Erich Michel: University of Zürich, Winterthurerstrasse
Wenzhao Dai: University of Zürich, Winterthurerstrasse
Thomas Müntener: University of Basel, St. Johanns-Ring 19
Patrick Ernst: University of Zürich, Winterthurerstrasse
Daniel Häussinger: University of Basel, St. Johanns-Ring 19
Andreas Plückthun: University of Zürich, Winterthurerstrasse
Oliver Zerbe: University of Zürich, Winterthurerstrasse

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Ultra-tight binding is usually observed for proteins associating with rigidified molecules. Previously, we demonstrated that femtomolar binders derived from the Armadillo repeat proteins (ArmRPs) can be designed to interact very tightly with fully flexible peptides. Here we show for ArmRPs with four and seven sequence-identical internal repeats that the peptide-ArmRP complexes display conformational dynamics. These dynamics stem from transient breakages of individual protein-residue contacts that are unrelated to overall unbinding. The labile contacts involve electrostatic interactions. We speculate that these dynamics allow attaining very high binding affinities, since they reduce entropic losses. Importantly, only NMR techniques can pick up these local events by directly detecting conformational exchange processes without complications from changes in solvent entropy. Furthermore, we demonstrate that the interaction surface of the repeat protein regularizes upon peptide binding to become more compatible with the peptide geometry. These results provide novel design principles for ultra-tight binders.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43596-2

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DOI: 10.1038/s41467-023-43596-2

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