De Novo Design of Protein Conformational Changes and Protein-Peptide Interactions

Abstract

This work addresses two difficult challenges in protein design: designing proteins with two distinct, interconvertible structural conformations and designing proteins to bind tightly to biologically active, flexible helical peptides. First, through the design of “hinge” proteins that can switch between two fully structured conformations in response to an effector-binding event, we demonstrate the modular transformation of biochemical information. Through detailed structural and biophysical characterization, we show tight coupling between the conformational change and the effector binding. Second, we present methods for designing proteins to bind helical peptides, which we show bind specifically to therapeutically relevant targets with nanomolar and picomolar affinities. These two approaches go beyond the single-structure paradigm in protein design and enable new possibilities for therapeutics and bioengineering.