CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot 76100, Israel.
Molecules. 2017 Aug 10;22(8):1324. doi: 10.3390/molecules22081324.
Functions of biomolecules, in particular enzymes, are usually modulated by structural fluctuations. This is especially the case in a gated diffusion-controlled reaction catalyzed by an enzyme such as acetylcholinesterase. The catalytic triad of acetylcholinesterase is located at the bottom of a long and narrow gorge, but it catalyzes the extremely rapid hydrolysis of the neurotransmitter, acetylcholine, with a reaction rate close to the diffusion-controlled limit. Computational modeling and simulation have produced considerable advances in exploring the dynamical and conformational properties of biomolecules, not only aiding in interpreting the experimental data, but also providing insights into the internal motions of the biomolecule at the atomic level. Given the remarkably high catalytic efficiency and the importance of acetylcholinesterase in drug development, great efforts have been made to understand the dynamics associated with its functions by use of various computational methods. Here, we present a comprehensive overview of recent computational studies on acetylcholinesterase, expanding our views of the enzyme from a microstate of a single structure to conformational ensembles, strengthening our understanding of the integration of structure, dynamics and function associated with the enzyme, and promoting the structure-based and/or mechanism-based design of new inhibitors for it.
生物分子的功能，特别是酶的功能，通常受到结构波动的调节。在酶（如乙酰胆碱酯酶）催化的门控扩散控制反应中尤其如此。乙酰胆碱酯酶的催化三联体位于一个狭长峡谷的底部，但它能催化神经递质乙酰胆碱的极快速水解，其反应速率接近扩散控制极限。计算建模和模拟在探索生物分子的动力学和构象特性方面取得了相当大的进展，不仅有助于解释实验数据，还能深入了解生物分子在原子水平上的内部运动。鉴于乙酰胆碱酯酶具有非常高的催化效率，以及在药物开发中的重要性，人们已经做出了巨大的努力，通过使用各种计算方法来理解与其功能相关的动力学。在这里，我们对乙酰胆碱酯酶的最近的计算研究进行了全面综述，将我们对酶的认识从单一结构的微状态扩展到构象 ensemble，加深了我们对与酶相关的结构、动力学和功能整合的理解，并促进了基于结构和/或基于机制的新型抑制剂的设计。
