Zinc Chelation with Hydroxamate in Histone Deacetylases Modulated by Water Access to the Linker Binding Channel

Abstract

It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylases (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity was revealed, but has not been understood. Herein with Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disapproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggested a novel mechanism that the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes the importance and gives guidance regarding the linker design for the development of new class-IIa specific HDAC inhibitors.

Inhibition and Mechanism of HDAC8 Revisited

“…As shown in Figure 3 left, optimization of model 1 leads to a structure very similar to the one obtained by Zhang and co-workers 31 where the hydroxamic acid remains uncharged. However, optimization of model 2 leads to a spontaneous proton transfer from SAHA to the nearby histidine H142 with very little reorganization of the remaining QM region.…”

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

“…The HDAC8 H143A mutant has an almost complete loss of activity in contrast to the residual activity of an H142A mutant, in concordance with the proposed model of action (Gantt et al 2010). Furthermore, quantum mechanical/molecular mechanical molecular dynamics simulations suggest that a neutral H143 first serves as the general base to accept a proton from the zincbound water molecule in the initial rate-determining nucleophilic attack step, and then shuttles it to the amide nitrogen atom to facilitate the cleavage of the amide bond (Wu et al 2011). This model seems to be a more likely catalytic mechanism for HDAC-related enzymes, which is similar to the conventional metalloenzymes thermolysin and carboxypeptidase A.…”

Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase Inhibition Activity of Hydroxamic Acid Derivatives

“…The active site comprises a narrow pocket located deep within the protein and contains the zinc metal cofactor. The metal was pentacoordinated by His183, Asp181, and Asp269 [32]. Docking results also showed a bidentate coordination through the carbonyl and hydroxyl groups of the ligand hydroxamate moieties (Fig.…”

“…The 3D structures of the compounds were created and subsequently subjected to energy minimized to within an rms gradient of 0.1 kcal/mol/Å using MOE 2009.10 package, setting the force field to the 94s variant of the Merck molecular force field 94s [31]. Various studies have suggested negative hydroxamate-Zn 2+ coordination in the active site of HDACs [32] and linked with several experimental results. Therefore, the HA inhibitors were deprotonated after importing the 3D structures to MOE database.…”