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计算研究双活性位点在酶工程中的催化潜力。

Computational studies on the catalytic potential of the double active site for enzyme engineering.

机构信息

Department of Computational Biology and AI, Kcat Enzymatic Private Limited, #16, Ramakrishnappa Road, Cox Town, Bangalore, 560005, India.

Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysuru, 570015, India.

出版信息

Sci Rep. 2024 Aug 2;14(1):17892. doi: 10.1038/s41598-024-60824-x.

Abstract

Proteins possessing double active sites have the potential to revolutionise enzyme design strategies. This study extensively explored an enzyme that contains both a natural active site (NAS) and an engineered active site (EAS), focusing on understanding its structural and functional properties. Metadynamics simulations were employed to investigate how substrates interacted with their respective active sites. The results revealed that both the NAS and EAS exhibited similar minimum energy states, indicating comparable binding affinities. However, it became apparent that the EAS had a weaker binding site for the substrate due to its smaller pocket and constrained conformation. Interestingly, the EAS also displayed dynamic behaviour, with the substrate observed to move outside the pocket, suggesting the possibility of substrate translocation. To gain further insights, steered molecular dynamics (SMD) simulations were conducted to study the conformational changes of the substrate and its interactions with catalytic residues. Notably, the substrate adopted distinct conformations, including near-attack conformations, in both the EAS and NAS. Nevertheless, the NAS demonstrated superior binding minima for the substrate compared to the EAS, reinforcing the observation that the engineered active site was less favourable for substrate binding due to its limitations. The QM/MM (Quantum mechanics and molecular mechanics) analyses highlight the energy disparity between NAS and EAS. Specifically, EAS exhibited elevated energy levels due to its engineered active site being located on the surface. This positioning exposes the substrate to solvents and water molecules, adding to the energy challenge. Consequently, the engineered enzyme did not provide a significant advantage in substrate binding over the single active site protein. Further, the investigation of internal channels and tunnels within the protein shed light on the pathways facilitating transport between the two active sites. By unravelling the complex dynamics and functional characteristics of this double-active site protein, this study offers valuable insights into novel strategies of enzyme engineering. These findings establish a solid foundation for future research endeavours aimed at harnessing the potential of double-active site proteins in diverse biotechnological applications.

摘要

具有双活性位点的蛋白质有可能彻底改变酶设计策略。本研究广泛探索了一种既包含天然活性位点 (NAS) 又包含工程化活性位点 (EAS) 的酶,重点研究其结构和功能特性。元动力学模拟用于研究底物如何与其各自的活性位点相互作用。结果表明,NAS 和 EAS 都表现出相似的最低能量状态,表明结合亲和力相当。然而,显然由于较小的口袋和受限的构象,EAS 对底物的结合位点较弱。有趣的是,EAS 还表现出动态行为,观察到底物移出口袋外,表明存在底物易位的可能性。为了获得更深入的见解,进行了导向分子动力学 (SMD) 模拟以研究底物的构象变化及其与催化残基的相互作用。值得注意的是,底物在 EAS 和 NAS 中均采用了不同的构象,包括接近攻击构象。然而,NAS 表现出对底物更好的结合极小值,与观察到的工程化活性位点对底物结合不利的结果一致,这是由于其限制导致的。QM/MM(量子力学和分子力学)分析突出了 NAS 和 EAS 之间的能量差异。具体而言,由于工程化的活性位点位于表面,EAS 表现出升高的能级。这种定位使底物暴露于溶剂和水分子中,增加了能量挑战。因此,与具有单一活性位点的蛋白质相比,工程化酶在底物结合方面并没有提供显著优势。此外,对蛋白质内部通道和隧道的研究揭示了促进两个活性位点之间物质传输的途径。通过揭示这种双活性位点蛋白质的复杂动力学和功能特征,本研究为酶工程的新策略提供了有价值的见解。这些发现为未来旨在利用双活性位点蛋白质在各种生物技术应用中的潜力的研究奠定了坚实的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fce6/11297320/de4628ddeac6/41598_2024_60824_Fig1_HTML.jpg

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