Unraveling the Interplay between Stability and Flexibility in the Design of Polyethylene Terephthalate (PET) Hydrolases,Journal of Chemical Information and Modeling

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Unraveling the Interplay between Stability and Flexibility in the Design of Polyethylene Terephthalate (PET) Hydrolases
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-09-13 , DOI: 10.1021/acs.jcim.4c00877
Shiqinrui Xu ₁ , Chengze Huo ₁ , Xiakun Chu _{1,

2,

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Affiliation

The accumulation of polyethylene terephthalate (PET), a widely used polyester plastic in packaging and textiles, has led to a global environmental crisis. Biodegradation presents a promising strategy for PET recycling, with PET hydrolases (PETase) undertaking the task at the molecular level. Unfortunately, PETase operates only at ambient temperatures with low efficiency, limiting its industrial application. Current engineering efforts focus on enhancing the thermostability of PETase, but increased stability can reduce the structural dynamics needed for substrate binding, potentially slowing enzymatic activity. To elucidate the balance between stability and flexibility in optimizing PETase catalytic activity, we performed theoretical investigations on both wild-type PETase (WT-PETase) and a thermophilic variant (Thermo-PETase) using molecular dynamics simulations and frustration analysis. Despite being initially designed to stabilize the native structure of the enzyme, our findings reveal that Thermo-PETase exhibits an unprecedented increase in structural flexibility at the PET-binding and catalytic sites, beneficial for substrate recruitment and product release, compared to WT-PETase. Upon PET binding, we observed that the structural dynamics of Thermo-PETase is largely quenched, favoring the proximity between the catalytic residues and the carbonyl of the PET substrate. This may potentially contribute to a higher probability of a catalytic reaction occurring in Thermo-PETase compared to WT-PETase. We suggest that Thermo-PETase can exhibit higher PET-degradation performance than WT-PETase across a broad temperature range by leveraging stability and flexibility at high and low temperatures, respectively. Our findings provide valuable insights into how PETase optimizes its enzymatic performance by balancing stability and flexibility, which may contribute to future PETase design strategies.

中文翻译：

揭示聚对苯二甲酸乙二醇酯（PET）水解酶设计中稳定性和柔韧性之间的相互作用

聚对苯二甲酸乙二醇酯（PET）是一种广泛用于包装和纺织品的聚酯塑料，其积累导致了全球环境危机。生物降解为 PET 回收提供了一种很有前途的策略，PET 水解酶（PETase）在分子水平上承担了这项任务。遗憾的是，PETase 仅在环境温度下运行，效率低，限制了其工业应用。目前的工程工作侧重于增强 PETase 的热稳定性，但稳定性的提高会降低底物结合所需的结构动力学，从而可能减慢酶活性。为了阐明优化 PETase 催化活性的稳定性和灵活性之间的平衡，我们使用分子动力学模拟和挫折分析对野生型 PETase （WT-PETase）和嗜热变体（Thermo-PETase）进行了理论研究。尽管最初旨在稳定酶的天然结构，但我们的研究结果表明，与 WT-PETase 相比，Thermo-PETase 在 PET 结合和催化位点的结构柔韧性表现出前所未有的增加，有利于底物募集和产物释放。在 PET 结合后，我们观察到 Thermo-PETase 的结构动力学在很大程度上被淬灭，有利于催化残基和 PET 底物的羰基之间的接近。与 WT-PETase 相比，这可能会导致 Thermo-PETase 发生催化反应的可能性更高。我们认为，Thermo-PETase 分别利用高温和低温下的稳定性和柔韧性，在较宽的温度范围内表现出比 WT-PETase 更高的 PET 降解性能。我们的研究结果为 PETase 如何通过平衡稳定性和灵活性来优化其酶性能提供了有价值的见解，这可能有助于未来的 PETase 设计策略。

更新日期：2024-09-13

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