Intrinsic Dynamics of the Binding Rail and Its Allosteric Effect in the Class I Histone Deacetylases.

The development of novel isoform/class-selective inhibitors is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylase (HDAC) drugs. The first potent HDAC allosteric inhibitor was discovered last year, and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanism and its remote regulatory effects on the catalytic/inhibitor activity of HDAC are still unclear. In this work, on the basis of microsecond-time-scale all-atom molecular dynamics (MD) simulations and picosecond-time-scale density functional theory/molecular mechanics MD simulations on HDAC8, we propose that the allostery is achieved by the intrinsic conformational flexibility of the binding rail (constituted by a highly conserved X-D residue dyad), which steers the loop-loop motion and creates the diverse shapes of the allosteric sites in different HDAC isoforms. Additionally, the rotatability of the binding rail is an inherent structural feature that regulates the hydrophobicity of the linker binding channel and thus further affects the HDAC enzyme inhibitory/catalytic activity by utilizing the promiscuity of X-D dyad. Since the plastic X residue is different among class I HDACs, these new findings provide a deeper understanding of the allostery, which is guidable for the design of new allosteric inhibitors toward the allosteric site and structure modifications on the conventional inhibitors binding into the active pocket by exploiting the intrinsic dynamic features of the conserved X-D dyad.