Achieving cell permeability and oral bioavailability for PROTACs is challenging as they reside in chemical spaces far beyond traditional molecular space. Efficient approaches for predicting proteolysis targeting chimeras (PROTACs) cell permeability are the major interest to reduce resource-demanding synthesis and testing of low-permeable PROTACs. Aim of this project is to identify biologically relevant conformations and insight into the origin of the differences in cell permeability of a set of VHL-based PROTACs (see detail in the attachment), in particular, we will investigate 1) if our approaches can be further validated with diverse PROTACs (proteolysis-targeting chimeras) in particular VHL-based PROTACs which are known to be complex and a large in size, 2) use all-atom molecular dynamics to simulate how the PROTACs partition from the aqueous phase into a lipid membrane, and 3) compare the conformational preference of VHL-based PROTACs with ensembles determined by NMR spectroscopy in apolar solution (CDCl3) to determine which method provides the best approximation of the solution ensembles. This project will take a major leap toward the prediction of the conformational ensembles of PROTACs that behave as molecular chameleons, and thereby toward the prediction of their properties. Overall, it will provide the first scientific basis for rational design of orally absorbed PROTACs in this uncharted chemical space.