The vital role of protein conformational sampling in detecting hidden or unformed covalent ligandable sites was assessed using an advanced platform designed to consider protein conformational fluctuations (Figure ). When tested on the same data set of holo sites, the advanced covalent ligandability assessment platform performed remarkably by correctly detecting >99% of these sites. This distinct performance is similarly reflected on apo sites data where the advanced ligandability assessment platform was able to capture 94% of the covalent ligandable sites on apo protein structures. The binding sites on apo proteins correspond to the liganded site on their holo structure counterparts. Since applications of conformational sampling of proteins is expected to widen of existing pockets or reveal subpockets thereby decreasing average distance between pocket surface and covalently modified residue in the PDB structure (Suppl. Figure ), a distance threshold of 9Å was used by the advanced ligandability assessment platform. Overall, in going from the simplistic distance computation approach (Suppl. Figure ) to the advanced platform (Figure ), a distance shift (0.5Å to 2.0Å) in the average distribution of residue-to-pocket distances and a shift in the relative number of sites towards the lower distance interval bins occur across the datasets. Decrease in the average residue-to-pocket distance incurred by opening or widening of pockets is more obvious when comparing apo and cryptic dataset across the two platforms.