The evolution of multiple active site configurations in a designed enzyme.
The evolution of multiple active site configurations in a designed enzyme.
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DOI：
10.1038/s41467-018-06305-y
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发表时间：
2018-09-25
影响因子：
16.6
通讯作者：
Jackson CJ
中科院分区：
文献类型：
--
作者：
Hong NS;Petrović D;Lee R;Gryn'ova G;Purg M;Saunders J;Bauer P;Carr PD;Lin CY;Mabbitt PD;Zhang W;Altamore T;Easton C;Coote ML;Kamerlin SCL;Jackson CJ
计算化学、生物信息学和实验室进化的发展促进了酶的从头设计和催化优化。除了创造有用的催化剂外，设计酶的产生和迭代改进可以为许多被认为有助于催化的现象之间的相互作用提供有价值的见解。在这项工作中，我们遵循构象采样，静电预组织，量子隧穿沿着进化轨迹的设计肯普消除酶的变化。我们观察到，在肯普Eliminase KE 07中，设计的活性位点的不稳定性导致两个额外的活性位点构型的出现。进化的构象选择然后逐渐稳定最有效的构型，导致改进的酶。这项工作阐明了构象可塑性和进化性之间的联系，并证明了远离酶活性位点的残基在控制和塑造有效催化的活性位点方面起着至关重要的作用。设计的酶的生成和迭代优化可以为更有效的催化提供有价值的见解。在这里，作者已经遵循了设计的肯普消除酶的迭代改进，并表明远程点突变可以通过大量的构象重组来重塑设计的活性位点。
Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis. Generation and iterative optimization of designed enzymes can provide valuable insights for a more efficient catalysis. Here the authors have followed the iterative improvement of a designed Kemp eliminase and show that remote point mutations could remodel the designed active site via substantial conformational reorganization.
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影响因子：
15
作者：
Alexandrova, Anastassia N.;Roethlisberger, Daniela;Baker, David;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
1.7
作者：
Bussi, Giovanni
通讯作者：
Bussi, Giovanni
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.3
作者：
Bhowmick, Asmit;Sharma, Sudhir C.;Head-Gordon, Teresa
通讯作者：
Head-Gordon, Teresa
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk