Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

Abstract

Histone deacetylase (HDAC) inhibitors have recently attracted considerable interest because of their therapeutic potential for the treatment of cell proliferative diseases. An X-ray structure of a very potent inhibitor, Trichostatin A (TSA), bound to HDLP (an HDAC analogue isolated from Aquifex aeolicus), is available. From this structure, an active site model (322 atoms), relevant for the binding of TSA and structural analogues, has been derived, and TSA has been minimized in this active site at HF 3-21G* level. The resulting conformation is in excellent accordance with the X-ray structure, and indicates a deprotonation of the hydroxamic acid in TSA by His 131. Also, a water molecule was minimized in the active site. In addition to a similar deprotonation, in accordance with a possible catalytic mechanism of HDAC as proposed by Finnin et al. (M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind and P. A. Marks, Nature, 1999, 401, 188-193), a displacement of the resulting OH- ion in the active site was observed. Based on these results, the difference in energy of binding between TSA and water was calculated. The resulting value is realistic in respect to experimental binding affinities. Furthermore, the mechanism of action of the His 131-Asp 166 charge relay system was investigated. Although the Asp residue in this motif is known to substantially increase the basicity of the His residue, no proton transfer from His 131 to Asp 166 was observed on binding of TSA or water. However, in the empty protonated active site, this proton transfer does occur.

Crystal Structure of a Bacterial Class 2 Histone Deacetylase Homologue

“…34,35 This is further supported by ab initio calculations suggesting the existence of a functional inner HisAsp charge transfer relay system. 36 Mutation of zinc ligand His182 completely abolishes activity (data not shown), confirming previous results which indicate an essential role of the enzyme-bound zinc cation. 17 Mutation of the active site tyrosine (Tyr312) was also shown to abolish catalytic activity supporting the view that this residue has an important function in the catalytic mechanism (C.H.…”

“…A major difference found between FB188 HDAH, HDLP and HDAC8 lies within the connecting region between a1 and a3 (amino acid residues [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. In both crystal forms of FB188 HDAH these regions make contacts to another molecule of the asymmetric unit thus stabilizing the structure; in solution this part may be flexible and may change conformation upon binding to or interacting with another protein.…”

Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2

“…Crystallographic studies have shown a zinc-dependent deacetylation catalyzed by HDLP (21). TSA mimicking the acetylated lysine has been shown to chelate the zinc in the catalytic pocket of HDLP by its hydroxamic acid (44). Our computational simulation revealed that TSA also nicely packs into the catalytic pocket of mammalian HDAC2 (Fig.…”

Homology modeling, force field design, and free energy simulation studies to optimize the activities of histone deacetylase inhibitors

“…In relation to the importance of the enzymeinhibitor environment in zinc coordination, Vanommeslaeghe et al have reported that more reliable force field parameters can be obtained with geometry optimization and population analysis on an extended model system at a modest level of theory [42]. Therefore, we carried out semiempirical PM3 and AM1 calculations with the MOPAC program as an effort to improve the potential parameters for the active site zinc complex of HDLP.…”