Chameleonicity Beyond Compactness: Conformational Persistence and Passive Permeability Across 20 PROTAC Ensembles
Proteolysis-targeting chimeras (PROTACs) are large, flexible molecules that frequently extend beyond conventional drug-like chemical space, including Lipinski's rule-of-five boundaries. Their membrane permeability has often been linked to molecular chameleonicity and the ability to adopt compact conformations with reduced polar surface exposure; however, the underlying conformational determinants…
Proteolysis-targeting chimeras, or PROTACs, are complex molecules that often exceed the size constraints typically associated with drug-like compounds. Their ability to permeate biological membranes has been associated with their flexibility, as they can adopt compact structures with reduced surface exposure. However, the specific factors that determine a PROTAC's permeability remain unknown.
To address this, researchers investigated 20 PROTACs that varied in their ability to passively diffuse through cell membranes. They used enhanced-sampling molecular dynamics simulations to study these molecules.
Despite all the permeability classes being able to achieve compact states with reduced radius of gyration and polar surface area, these characteristics alone were not sufficient to differentiate between permeable and non-permeable PROTACs. To better understand the structural basis of permeability, the researchers introduced a new metric called maximum ring size (MRS).
MRS measures the size of the largest intramolecular hydrogen-bonded ring within a PROTAC. Like the other descriptors analyzed, MRS did not effectively separate or rank the different permeability classes. However, MRS proved useful in locating compact conformations within the large ensemble of PROTAC structures.
The researchers then examined representative compact conformations of selected PROTACs using unbiased molecular dynamics simulations in both water and chloroform environments. They found that highly permeable PROTACs adopted a closed-flat conformation in both environments, but in two distinct arrangements. In contrast, less permeable compounds displayed a more heterogeneous distribution of conformations.
This suggests that the ability of a PROTAC to passively diffuse through cell membranes depends on the presence, stability, and environment-dependent persistence of permeable-like states. Compactness alone does not determine a PROTAC's permeability, but rather the population and stability of permeable-like conformations.
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