【摘要】
定向进化和理性设计是两种常见的酶分子改造策略。定向进化策略已经被成功应用于酶活性、稳定性、底物特异性、立体选择性等性质的改造，并因此被授予了2018 年诺贝尔化学奖。然而，定向进化需要构建大规模的突变体文库，建立高通量筛选手段，并耗费大量的人力，物力以及财力。定向进化方法也难以完成对序列空间的全面搜索，存在根本缺陷。理性设计策略依靠对蛋白质结构与功能关系的认识预测可能的突变型，而后通过定点突变的手段在目的基因中构建突变型。从本质上说，与定向进化相比，理性设计改造蛋白质的效率更高。另外，理性设计方法具有普适性，一种有效理性设计策略可以普遍应用于多种蛋白质的改造。然而，目前理性设计方法的准确率普遍较低，应用范围远没有定向进化广泛。本人近年来从事开发理性设计方法用于酶的改造研究。在此次报告中，我将介绍自己取得的一些成果。具体包括：发展基于“柔性”的理性设计策略以提高酶稳定性[1-2]；利用分子动力学模拟探究长距离点突变之间相互作用机制[3]；以及开发理性设计策略克服酶分子活性与稳定性之间的“trade-off”[4]。
Reference:
[1]Haoran Yu,He Huang. “Engineering Proteins for Thermostabilitythrough Rigidifying Flexible Sites (RFS).” Biotechnology Advances 32.2 (2014):308-315.
[2]Haoran Yu, YihanYan, Cheng Zhang, Paul A. Dalby. “Two strategies to engineer flexible loops forimproved enzyme thermostability.” Scientific Reports 7, Article number: 41212(2017) doi:10.1038/srep41212.
[3] HaoranYu, Paul A. Dalby. “Coupled molecular dynamicsmediate long and short-range epistasis between mutations that affect stabilityand aggregation kinetics.” Proceedingsof the National Academy of Sciences 115, no. 47 (2018): E11043-E11052.
[4] HaoranYu, Paul A. Dalby. “Exploiting correlatedmolecular-dynamics networks to counteract enzyme activity-stability trade-off.”Proceedings of the National Academy ofSciences 115, no. 52 (2018): E12192-E12200.
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