Conformational dynamics in the membrane interactions of bispecific targeted degrader therapeutics

Proteolysis targeting chimeras (PROTACs) offer vast new therapeutic opportunities, however their physicochemical properties are difficult to combine with optimal cell permeability and exposure at the target sites. We have systematically analyzed a dataset of more than 3500 PROTACs to investigate how the choice of ubiquitin E3 ligase ligands, linker design, and global molecular properties can be optimized to achieve the desired cell permeability and intracellular exposure. We find that conformational flexibility leads to environment-dependent shielding of polar functions and improved interactions with cell membranes, but that at the same time extended, linear conformations within the membrane are beneficial. Linker composition was a major factor in determining the folding propensity. Collectively, our results suggest that strategies to rationally design linkers and to shield polarity selectively within the protein-of-interest (POI) ligand and/or E3 ligand domains, rather than more extensive folding, may be beneficial in the design of permeable and effective PROTACs.