LAUSR

A newly synthesized small molecule, KTT‐1, exhibits kinetically selective inhibition of histone deacetylase 2, HDAC2, over its homologous enzyme, HDAC1. KTT‐1 is hard to be released from the HDAC2/KTT‐1 complex, compared to the HDAC1/KTT‐1 complex and the residence time of KTT‐1 in HDAC2 is longer than that in HDAC1. To explore the physical origin of this kinetic selectivity, we performed replica‐exchange umbrella sampling molecular dynamics simulations for formation of both complexes. The calculated potentials of mean force suggest that KTT‐1 is stably bound to HDAC2 and that it is easily disassociated from HDAC1. In the direct vicinity of the KTT‐1 binding site in both enzymes, there exists a conserved loop consisting of four consecutive glycine residues (Gly304‐307 for HDAC2; Gly299‐302 for HDA1). The difference between the two enzymes comes from a single un‐conserved residue behind this loop, namely, Ala268 in HDAC2 and Ser263 in HDAC1. The Ala268 contributes to the tight binding of KTT‐1 to HDAC2 by the linear orientation of Ala268, Gly306, and one carbon atom in KTT‐1. On the other hand, Ser263 cannot stabilize the binding of KTT‐1 to HDAC1, because it is relatively further away from the glycine loop and because the directions of the two forces are not in line.