Department of Chemistry and State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, China.
J Am Chem Soc. 2011 Apr 27;133(16):6110-3. doi: 10.1021/ja111104p. Epub 2011 Apr 1.
It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD 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 disproved 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 suggest a novel mechanism in which 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 its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors.
开发具有类别和同工型选择性的组蛋白去乙酰化酶（HDAC）调节剂具有重要的生物学意义和医学重要性。连接子组件对 HDAC 抑制特异性的影响已经被揭示出来，但尚未被理解。使用 Born-Oppenheimer 从头算 QM/MM MD 模拟，这是一种模拟金属酶的最先进方法，我们发现，当羟肟酸与 HDAC8 结合时，其仍然保持质子化状态，从而否定了这样一种机制假说，即两个 HDAC 亚类之间不同的锌-羟肟酸螯合模式来自于羟肟酸的不同质子化状态。相反，我们的模拟表明了一种新的机制，其中羟肟酸与 HDAC 中锌离子的螯合模式通过连接子结合通道中水的进入来调节。这种对连接子结合与锌螯合之间相互作用的新见解强调了其重要性，并为新型 IIa 类特异性 HDAC 抑制剂的开发提供了连接子设计方面的指导。
