Macrocyclic probes (CycH_8, CycH_10, CycH_12) reach maximum VCAVITY quickly, and higher energy conformers are unable to continue to parametrize additional space by further window increases beyond 5.0 kcal/mol. These probes are more constrained in shape, generally resulting in more regular, spherical pockets. Acyclic probes (AcycH_8, AcycH_10, AcycH_12) explore more space (larger VCAVITY) with higher conformer energy windows. The flexibility and narrow side arms of acyclic probes can access smaller cavities within a pocket of interest, such as