限域效应增强酶本征活性的分子机制

doi:10.1016/S1872-2067(25)64827-3

催化学报 ›› 2026, Vol. 81: 355-365.DOI: 10.1016/S1872-2067(25)64827-3

限域效应增强酶本征活性的分子机制

曹宇飞^a^,^b^,^c^,¹(), 陈爽^d^,¹, 梁慧^a^,¹, 杨骏荣^a, 娄文勇^a, 戈钧^b^,^c()

^a 华南理工大学食品科学与工程学院, 应用生物催化实验室, 广东广州 510640, 中国
^b 清华大学化学工程系, 工业生物催化教育部重点实验室, 北京 100084, 中国
^c 绿色生物制造全国重点实验室, 北京 100084, 中国
^d 伦敦大学学院药学院, 伦敦, 英国

收稿日期:2025-07-15 接受日期:2025-08-25 出版日期:2026-02-18 发布日期:2025-12-26
通讯作者: *电子信箱: yufeicao@scut.edu.cn (曹宇飞),junge@mail.tsinghua.edu.cn (戈钧).
作者简介:¹共同第一作者.
基金资助:
国家重点研发计划(2023YFA0913600);国家自然科学基金(22408113);国家自然科学基金(22425803);中央高校基本科研业务费(2024ZYGXZR078);广州市科技计划项目(2025A04J3891);北京市自然科学基金(Z240030);深圳市科技计划(KCXFZ20240903093102004)

Mechanism of confinement enhancing enzyme intrinsic activity

Yufei Cao^a^,^b^,^c^,¹(), Shuang Chen^d^,¹, Hui Liang^a^,¹, Junrong Yang^a, Wenyong Lou^a, Jun Ge^b^,^c()

^a Lab of Applied Biocatalysis, School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China.
^b Key Lab of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
^c State Key Laboratory of Green Biomanufacturing, Beijing 100084, China
^d Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College London, London WC1N 1AX, United Kingdom

Received:2025-07-15 Accepted:2025-08-25 Online:2026-02-18 Published:2025-12-26
Contact: *E-mail: yufeicao@scut.edu.cn (Y. Cao),junge@mail.tsinghua.edu.cn (J. Ge).
About author:¹Contributed equally to this work.
Supported by:
National Key R&D Program of China(2023YFA0913600);National Natural Science Foundation of China(22408113);National Natural Science Foundation of China(22425803);Fundamental Research Funds for the Central Universities(2024ZYGXZR078);Science and Technology Projects in Guangzhou(2025A04J3891);Beijing Natural Science Foundation(Z240030);Shenzhen Science and Technology Program(KCXFZ20240903093102004)

摘要/Abstract

摘要：

酶在表面或空间限域环境中发挥催化作用在细胞内和细胞外的催化应用中都十分常见. 细胞内的限域环境和分子拥挤效应会显著影响底物扩散和传递及酶的本征催化活性, 精细调控复杂的级联反应网络. 在细胞外催化中通常利用DNA, RNA, 蛋白质, 金属-有机框架等多种材料构筑限域微环境, 这些材料能有效增强酶的稳定性, 提高催化效率并实现酶的重复使用. 此外, 特定材料诱导的酶构象变化与材料-酶之间的相互作用, 能进一步提高酶的催化活性. 尽管细胞内外限域催化现象广泛存在, 但限域微环境如何调控酶的本征活性, 其分子机制仍需进一步深入探索.

本文探讨了空间限域对酶催化活性的调控机制, 并通过实验与理论计算揭示了其普适性与应用潜力. 首先, 为模拟细胞内的拥挤环境, 在Bacillus subtilis lipase A(BSLA)催化过程中引入不同的聚合物拥挤剂; 结果显示, 在25和40 °C条件下酶活性均表现出提升的趋势. 这表明限域环境能有效增强BSLA的催化活性. 为揭示其分子机制, 采用QM/MM(EVB方法)对BSLA的催化过程进行模拟; 结果显示, BSLA在自由状态下的活化自由能(ΔG^‡)与实验值相吻合, 而在表面loop柔性区域施加空间限域后, ΔG^‡表现出降低的趋势. 多位点施加限域可进一步降低ΔG^‡. 热力学分析表明, 限域既能降低活化焓, 也能减少由构象波动带来的熵损失, 从而整体降低自由能能垒. 结构分析进一步揭示限域促进了关键氢键网络的稳定, 减少了过渡态波动, 使活性位点预组织更加合理, 过渡态更加稳定. 基于这些结果, 提出了利用反应初态和过渡态结构波动的差异筛选潜在限域施加位点的策略. 通过计算发现多个loop区域的限域可以显著降低活化自由能, 熵效应贡献尤为突出. 进一步的计算模拟验证了在酶催化的不同步骤中限域均能降低过渡态的能垒, 说明限域效应在整个催化循环中均具有积极作用. 该方法不仅适用于BSLA, 也可推广至其他酶体系如PET降解酶IsPETase.

综上, 本文结合实验与计算机模拟系统深入地研究了表面限域对酶催化本征活性的影响, 并发现其催化活性提升的驱动力同时来自焓效应和熵效应. 这种限域增强效应受天然生物体系限域催化的启发, 为酶催化剂的设计提供了新的策略.

关键词: 酶催化, 表面限域, 经验价键计算, 活化自由能, 酶设计

Abstract:

Enzymatic catalysis within surface- and volume-confined environments is common in biological cells or industrial applications. Despite their prevalence both in vivo and in vitro, a comprehensive mechanistic understanding of how these confinements tune the intrinsic activity of enzymes has remained elusive. Herein, we explore the role of confinement in shaping the activity of enzymes. Experiments show that the confinements induced by macromolecular crowding enhance lipase activity. To uncover the origin of the activity enhancement, thermodynamic activation parameters of lipase catalysis were calculated through extensive molecular dynamics (MD) and empirical valence bond (EVB) simulations. The EVB approach has proven to be an efficient method, enabling extensive sampling via MD and the evaluation of thermodynamic activation parameters for enzyme catalysis. Our findings reveal that confinement applied at the loop regions of lipase leads to higher intrinsic activities, and this effect depends on the degree of confinement. The lower free energy of activation originates from the gain of both enthalpy and entropy. Better preorganization of the active site and greater conformational space overlap between initial and transition states enhance lipase catalysis. We observe that the catalytic enhancement due to surface confinement is not exclusive to lipase but extends to PETase, highlighting its potential universality as a principle for enzyme design and engineering.

Key words: Enzyme catalysis, Surface confinement, Empirical valence bond calculation, Activation free energy, Enzyme design

曹宇飞, 陈爽, 梁慧, 杨骏荣, 娄文勇, 戈钧. 限域效应增强酶本征活性的分子机制[J]. 催化学报, 2026, 81: 355-365.

Yufei Cao, Shuang Chen, Hui Liang, Junrong Yang, Wenyong Lou, Jun Ge. Mechanism of confinement enhancing enzyme intrinsic activity[J]. Chinese Journal of Catalysis, 2026, 81: 355-365.

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https://www.cjcatal.com/CN/Y2026/V81/I2/355

图/表 6

Fig. 1. (a) Illustration of confined enzyme catalysis in vivo and in vitro. (b) Relative activity of BSLA under confinements by adding different polymer crowders at 25 and 40 °C. The enzyme catalysis in buffer solutions without crowders is labeled as "Control". The designations "PEG_1", "PEG_2", "PVP_1", "PVP_2", "Ficoll_1", and "Ficoll_2" represent the addition of PEG6k (polyethylene glycol, molecular weight: 6000) at 1 mg/L, PEG6k at 5 mg/L, PVP40k (polyvinylpyrrolidone, molecular weight: 40000) at 5 mg/L, PVP58k at 1 mg/L, Ficoll70 at 1 mg/L, and Ficoll70 at 2 mg/L, respectively.

Fig. 2. Impact of surface confinement on BSLA intrinsic activity. (a) Structures of the enzyme-substrate (ES) complex, transition state (TS), and enzyme-product (EP) complex. Substrate pNPB and catalytic triad (Ser77-His156-Asp133) were shown. (b) Calculated free energy profiles (298.15 K) from reactants to the tetrahedral intermediate in the acylation step for the reference reaction in water (blue) and BSLA (red). (c) Position distribution of the 11 lysine residues located on the surface of BSLA is shown. Additionally, the catalytic triad comprising Ser77-His156-Asp133 is indicated. (d) Activation free energy ΔG? calculations for BSLA under lysine restraint at 323.15 K are presented. The wild BSLA, without restraint, is represented as "wild type". The designation "rK44" denotes restraint (confinement) applied at residue Lys44, and so forth. "4_r" encompasses Lys44, Lys69, Lys112, and Lys122 under restraint. "6_r" encompasses Lys44, Lys69, Lys70, Lys95, Lys112, and Lys122 under restraint. Data is presented in kcal/mol-1 as the average values and standard error of the mean.

Fig. 3. The origin of reduced activation free energy in BSLA due to surface confinement. (a) Arrhenius plots depicting ΔG?/T vs. 1/T for catalyzed reactions in wild type BSLA and the "6_r" BSLA variant. (b) A comparison of interatomic distances for four atom pairs within the transition states of wild BSLA and the "6_r" BSLA variant. (c) RMSF of both wild and confined BSLA at transition states. Dynamic structural ensembles of the ES and TS states for wild BSLA (d), and "6_r" BSLA variant (e), projected onto the eigenvectors corresponding to the two lowest-frequency principal components (PCA1 and PCA2).

Fig. 4. Rational confinement site selection for BSLA. (a) Differential ΔRMSF illustrating the disparity in conformational fluctuations between the ES and TS states of wild BSLA and the "6_r" variant. (b) Visualization of ΔRMSF of each residue. ΔRMSF values increase from blue to red. (c) Activation free energy ΔG? calculations for BSLA under restraint at 323.15 K are presented. The unrestrained wild-type BSLA is labeled as "wild type." The notation "rG13" signifies restraint (confinement) applied at residue Gly13, and so on. (d) Arrhenius plots depicting ΔG?/T vs. 1/T for catalyzed reactions in wild type BSLA and the "rF16&S131" BSLA variant.

Fig. 5. Impact of confinements on the deacylation of BSLA. (a) The deacylation step of BSLA catalyzing pNPB hydrolysis. IT1 represents the acylated BSLA, IT2 is the tetrahedral intermediate, and PC is the final deacylated state. (b) Calculated free energy profiles (323.15 K) from the acylated BSLA (IT1) to the final deacylated state (PC) during the deacylation step for both wild-type BSLA and the confined variant "rF16&S131". The intermediate formed between the two transition states (TS1 and TS2) was designated as IT2. (c) Differential ΔRMSF illustrating the disparity in conformational fluctuations between the IT1 and TS2 states of wild-type BSLA.

Fig. 6. Confinement enhancing IsPETase activity. (a) Visualization of ΔRMSF of each residue. (b) Calculated activation free energy of wild and confined IsPETase at rationally selected sites at 310 K.

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限域效应增强酶本征活性的分子机制

Mechanism of confinement enhancing enzyme intrinsic activity

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