合成生物学 ›› 2022, Vol. 3 ›› Issue (3): 567-586.DOI: 10.12211/2096-8280.2021-013
SIM Byuri, 赵一雷
收稿日期:
2021-01-27
修回日期:
2021-02-03
出版日期:
2022-06-30
发布日期:
2022-07-13
通讯作者:
赵一雷
作者简介:
基金资助:
Byuri SIM, Yilei ZHAO
Received:
2021-01-27
Revised:
2021-02-03
Online:
2022-06-30
Published:
2022-07-13
Contact:
Yilei ZHAO
摘要:
当今生物合成催化元件超进化分子理性设计的瓶颈在于有限的计算资源、研究时间与催化反应复杂势能面接近无穷无尽的计算需求之间的矛盾。然而,两个前所未有的数据集合有望拓新蛋白质工程人工智能化分子设计,其一是高通量定向进化实验带来的巨量高效突变体序列信息,其二是基于结构生物学的高阶量子力学计算所揭示的全原子飞秒精度反应机制。本文从催化基本理论、米氏复合物近进攻构象、催化循环效率控制点的角度浅析预反应态模型的基本概念和应用。预反应态模型尝试利用在低反应势垒生物化学反应中内禀的近进攻构象与过渡态具有相近的物理化学稳定性,弹性地选择与催化元件进化目标相关的关键过渡态,利用经典分子动力学模拟分析近过渡态的活性构象布居数与远端突变、底物结构、实验条件的关系。预反应态分析的基本流程为:首先,基于高阶量子力学反应势能面提取催化中心关键过渡态的结构特征;其次,从高精度蛋白质三维结构出发,结合氨基酸质子化生物信息学预测工具构建出关键过渡态对应的近进攻态活性构象;最后,利用过渡态结构特征设定分子动力学模拟初始约束条件,并逐步取消约束条件测试预反应态随氨基酸突变和底物变化的稳定性变化,以近进攻构象在预反应态轨迹中布居数作为“预反应态-酶活”半定量相关系数,从预反应态稳定性中挖掘酶与底物的适配图谱。当前在预反应态动态结构与酶活的定量关系分析上还有诸多难题亟待突破,利用高通量高阶量子化学再采样计算、结合机器学习人工智能分析代表了预反应态模型的发展方向。
中图分类号:
SIM Byuri, 赵一雷. 预反应态模型浅析:催化活性和近过渡态分子模拟[J]. 合成生物学, 2022, 3(3): 567-586.
Byuri SIM, Yilei ZHAO. Assessment on the pre-reaction state of enzyme: could we understand catalytic activity with near transition-state molecular dynamic simulation?-a review[J]. Synthetic Biology Journal, 2022, 3(3): 567-586.
图2 催化元件突变导致反应势能面微扰的示意图[在酶催化单步反应米氏模型中,预反应态与近进攻构象定义相同,米氏复合物热运动中接近反应过渡态(近进攻构象)活性构象的布居数p与催化活性正相关]
Fig. 2 Diagram for the perturbation of energy profile caused by the mutation of catalytic elements(In the simplest Michaelis's model, pre-reaction state and near attack conformation are identical, using the correlation of active conformation population and enzyme proficiency.)
图3 催化循环周转效率TOF与催化反应势能面的关系[在酶催化多步催化循环中,预反应态定义为关键决速步过渡态相关的活性构象的布居数p,它的变化与催化元件优化目标直接相关(如突变效应或底物适配)]
Fig. 3 Correlation of the turn-over frequency (TOF) and reaction potential energy surface(In multiple steps of a catalytic cycle, pre-reaction state is defined as the active conformation near rate-determining transition state, in which rate is dependent on the protein engineering target such as mutation effect and substrate diversity.)
图4 催化元件分子进化前后的反应势能面[进化完成前通常存在阶段性的最大控制点(左图),而进化后反应势能面各过渡态的控制度相近(右图)]
Fig. 4 Imaginary reaction potential energy surface for molecular evolution(Before evolving to a "perfect" enzyme, one point on the reaction potential energy surface controls the overall rate, but many other points are equivalently important for the perfect enzyme.)
研究对象 | 预反应态所选择的控制点 | 实例 |
---|---|---|
红霉素DEBS硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 与反应位点间隔4~5个化学键的碳原子对反应中心环化和水解活性结构的远程作用[ PRS结构参数:NH259-OH距离、OH-C距离 |
苦霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 12元和14元大环成环对反应中心环化和水解活性结构的影响[ PRS结构参数:NH268-OH距离、OH-C距离 |
变构霉素硫酯酶/苦霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 变构霉素生物合成时环化释放受阻,利用异源硫酯酶调整环化水解选择性,适配性分析[ 变构霉素硫酯酶PRS结构参数:NH255-OH距离、OH-C距离 苦霉素硫酯酶PRS结构参数:NH268-OH距离、OH-C距离 |
匹马霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 与反应位点间隔11~13个化学键的碳原子修饰对反应中心环化和水解活性结构的远程作用[ PRS结构参数:NH261-OH距离、OH-C距离 |
醇脱氢酶KpADH | 质子偶合的负氢原子转移关键过渡态 | 高效突变体与野生型反应中心的活性构象分布变化[ PRS结构参数:HY164-O距离、HNADPH-C距离 |
醇脱氢酶CpRCR | 质子偶合的负氢原子转移关键过渡态 | 高效突变体与野生型反应中心的活性构象分布变化[ PRS结构参数:HS46-O距离、HNADPH-C距离 |
DNA甲基化酶3A | SAM甲基转移到DNA-酶共价结合中间体 | 白血病高发的R882H远端突变对活性中心SAM甲基转移的影响[ PRS结构参数:CSAM-C距离 |
脱羧酶TyDC | PLP辅因子与底物的共价加合物C-C键断裂 | 通过H98、H251控制共价加合物的反应前线轨道布局[ PRS结构参数:CCαNSB角度,CCαNSBC4’二面角 |
酰胺水解酶NiHyuC | 碳四面体氧负离子关键过渡态 | 高效突变体对活化后巯基与被进攻的羧基反应前线轨道布局的影响[ PRS结构参数:SC171-C距离、SC171CO进攻角 |
普鲁兰多糖酶 | 取代反应SN2过渡态(碳氧键断裂) | 高效突变体对[O-C-O]取代反应前线轨道布局的影响[ PRS结构参数:OD619-C距离、OD619CO夹角 |
MERS和SARS冠状病毒主蛋白水解酶 | 碳四面体氧负离子关键过渡态 | 两种病毒主蛋白水解酶的关键反应前线轨道布局[ MERS病毒PRS结构参数:SC148-C距离、SC148CO进攻角 SARS病毒PRS结构参数:SC145-C距离、SC145CO进攻角 |
表1 预反应态模型的研究实例[95-98, 101,103,106,108,110,112,114]
Tab. 1 Pre-reaction states of the studied enzymes, control points, and geometric parameters[95-98, 101,103,106,108,110,112,114]
研究对象 | 预反应态所选择的控制点 | 实例 |
---|---|---|
红霉素DEBS硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 与反应位点间隔4~5个化学键的碳原子对反应中心环化和水解活性结构的远程作用[ PRS结构参数:NH259-OH距离、OH-C距离 |
苦霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 12元和14元大环成环对反应中心环化和水解活性结构的影响[ PRS结构参数:NH268-OH距离、OH-C距离 |
变构霉素硫酯酶/苦霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 变构霉素生物合成时环化释放受阻,利用异源硫酯酶调整环化水解选择性,适配性分析[ 变构霉素硫酯酶PRS结构参数:NH255-OH距离、OH-C距离 苦霉素硫酯酶PRS结构参数:NH268-OH距离、OH-C距离 |
匹马霉素硫酯酶 | 底物上载后共价复合物水解和环化途径选择 | 与反应位点间隔11~13个化学键的碳原子修饰对反应中心环化和水解活性结构的远程作用[ PRS结构参数:NH261-OH距离、OH-C距离 |
醇脱氢酶KpADH | 质子偶合的负氢原子转移关键过渡态 | 高效突变体与野生型反应中心的活性构象分布变化[ PRS结构参数:HY164-O距离、HNADPH-C距离 |
醇脱氢酶CpRCR | 质子偶合的负氢原子转移关键过渡态 | 高效突变体与野生型反应中心的活性构象分布变化[ PRS结构参数:HS46-O距离、HNADPH-C距离 |
DNA甲基化酶3A | SAM甲基转移到DNA-酶共价结合中间体 | 白血病高发的R882H远端突变对活性中心SAM甲基转移的影响[ PRS结构参数:CSAM-C距离 |
脱羧酶TyDC | PLP辅因子与底物的共价加合物C-C键断裂 | 通过H98、H251控制共价加合物的反应前线轨道布局[ PRS结构参数:CCαNSB角度,CCαNSBC4’二面角 |
酰胺水解酶NiHyuC | 碳四面体氧负离子关键过渡态 | 高效突变体对活化后巯基与被进攻的羧基反应前线轨道布局的影响[ PRS结构参数:SC171-C距离、SC171CO进攻角 |
普鲁兰多糖酶 | 取代反应SN2过渡态(碳氧键断裂) | 高效突变体对[O-C-O]取代反应前线轨道布局的影响[ PRS结构参数:OD619-C距离、OD619CO夹角 |
MERS和SARS冠状病毒主蛋白水解酶 | 碳四面体氧负离子关键过渡态 | 两种病毒主蛋白水解酶的关键反应前线轨道布局[ MERS病毒PRS结构参数:SC148-C距离、SC148CO进攻角 SARS病毒PRS结构参数:SC145-C距离、SC145CO进攻角 |
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