Physical Chemistry, Royal Institute of Technology (KTH), Stockholm, Sweden.
J Chem Inf Model. 2011 Aug 22;51(8):1906-17. doi: 10.1021/ci200177d. Epub 2011 Aug 3.
A computationally inexpensive design strategy involving 'semirational' screening for enzymatic catalysis is presented. The protocol is based on well-established computational methods and represents a holistic approach to the catalytic process. The model reaction studied here is the Diels-Alder, for which a successful computational design has recently been published (Siegel, J. B. et al. Science 2010, 329, 309-313). While it is a leap forward in the field of computational design, the focus on designing only a small fraction of the active site gives little control over dynamics. Our approach explicitly incorporates mutagenesis and the analysis of binding events and transition states, and a promising enzyme-substrate candidate is generated with relatively little effort. We estimate catalytic rate accelerations of up to 10⁵.
本文提出了一种计算成本低廉的设计策略，涉及酶催化的“半理性”筛选。该方案基于成熟的计算方法，代表了对催化过程的整体方法。这里研究的模型反应是 Diels-Alder 反应，最近已经成功地进行了计算设计（Siegel，JB 等人。科学 2010，329，309-313）。虽然这是计算设计领域的一个飞跃，但专注于仅设计活性位点的一小部分，对动力学的控制很小。我们的方法明确地包含了诱变和结合事件以及过渡态的分析，并且相对较少的努力就产生了有前途的酶-底物候选物。我们估计催化速率的加速高达 10⁵。
