Mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is a homotetramer assembled by two equivalent dimers, is an important enzyme that metabolizes ethanol-derived acetaldehyde to acetate in a coenzyme-dependent manner. The highly reactive acetaldehyde exhibits a toxic effect, indicating that the proper functioning of ALDH2 is essential to counteract aldehyde-associated diseases. It is known that the catalytic activity of ALDH2 is drastically impaired by a frequently observed mutation, E487K, in a dominant fashion. However, the molecular basis of the inactivation mechanism is elusive because of the complex nature of the dynamic behavior. Here, we performed microsecond-timescale molecular dynamics simulations of the proteins complexed with coenzymes. The E487K mutation elevated the conformational heterogeneity of the dimer interfaces, which are relatively distal from the substituted residue. Dynamic network analyses showed that Glu487 and the dimer interface were dynamically communicated, and the dynamic community further spanned throughout all of the subunits in the wild-type; however, this network was completely rearranged by the E487K mutation. The perturbation of the dynamic properties led to alterations of the global conformational motions and destabilization of the coenzyme binding required for receiving a proton from the catalytic nucleophile. The insights into the dynamic behavior of the dominant negative mutant in this work will provide clues to restore its function.

中文翻译：

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E487K 诱导的线粒体醛脱氢酶 2 功能相关动力学紊乱

线粒体醛脱氢酶 2 (ALDH2) 是一种由两个等效二聚体组装而成的同源四聚体，是一种重要的酶，可将乙醇衍生的乙醛以辅酶依赖性方式代谢为乙酸盐。高活性乙醛表现出毒性作用，表明 ALDH2 的正常功能对于对抗醛相关疾病至关重要。众所周知，ALDH2 的催化活性受到频繁观察到的 E487K 突变的显着影响。然而，由于动态行为的复杂性，失活机制的分子基础是难以捉摸的。在这里，我们对与辅酶复合的蛋白质进行了微秒级分子动力学模拟。E487K 突变提高了二聚体界面的构象异质性，与取代的残基相对较远。动态网络分析表明，Glu487 和二聚体界面是动态交流的，动态群落进一步跨越了野生型的所有亚基；然而，这个网络被 E487K 突变完全重新排列。动态特性的扰动导致整体构象运动的改变和从催化亲核试剂接收质子所需的辅酶结合的不稳定。在这项工作中对显性负突变体的动态行为的见解将为恢复其功能提供线索。动态群落进一步跨越野生型的所有亚基；然而，这个网络被 E487K 突变完全重新排列。动态特性的扰动导致整体构象运动的改变和从催化亲核试剂接收质子所需的辅酶结合的不稳定。在这项工作中对显性负突变体的动态行为的见解将为恢复其功能提供线索。动态群落进一步跨越野生型的所有亚基；然而，这个网络被 E487K 突变完全重新排列。动态特性的扰动导致整体构象运动的改变和从催化亲核试剂接收质子所需的辅酶结合的不稳定。在这项工作中对显性负突变体的动态行为的见解将为恢复其功能提供线索。