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Substrate-induced changes in dynamics and molecular motions of cuticle-degrading serine protease PL646: a molecular dynamics study

机译：皮层降解丝氨酸蛋白酶PL646的动力学和分子运动的底物诱导的变化：分子动力学研究

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摘要

Cuticle-degrading serine proteases secreted by nematophagous fungi can degrade the nematode cuticle during the infection processes. PL646, an alkaline cuticle-degrading serine protease derived from the nematophagous fungus Paecilomyces lilacinus, has been shown to have a high nematicidal activity. Although the crystal structure of PL646 provides a solid basis for investigating its structure-function relationship, the detailed aspects of the dynamics involving the substrate binding, orientation, catalysis, product release, and how these processes are regulated, remain unstudied. Molecular dynamics (MD) simulations and metadynamics simulations of PL646 with and without the peptide substrate AAPV were performed to investigate the changes in structure, molecular motions, and free energy landscape (FEL) of PL646 upon substrate binding. The results indicate that during simulations, the substrate-bound PL646 adopts a more stable and compact conformation than the substrate-free form. However, a few regions located opposite the substrate binding pockets or connected to the catalytic residue show increased flexibility upon substrate binding. Combined essential dynamics (ED) analysis reveals that, upon substrate binding, the noticeable displacements occur not only in the substrate binding pockets/sites, but also in the surface-exposed loops. The dynamic pockets caused by the large concerted motions are proposed to be linked to the substrate recognition, binding, orientation, catalysis, and product release of PL646. The constructed FELs reveal that the substrate-free PL646 has a more rugged and wider free energy surface, and a higher minimum free energy level than the proteinase in complex with its substrate, indicating that the substrate binding reduces the conformational flexibility while increasing the stability of PL646. The results presented in this work will facilitate a better understanding of the structure-dynamics-function relationship of the cuticle-degrading serine protease PL646.
机译：通过Nematophagous真菌分泌的角质层降解丝氨酸蛋白酶可以在感染过程中降解线虫角质层。 PL646是衍生自Nematophagous Feeggus paecilomyces Lilacinus的碱性角质层降解丝氨酸蛋白酶，已显示出具有高的血征性活性。尽管PL646的晶体结构为研究其结构功能关系提供了坚实的基础，但是涉及底物结合，取向，催化，产品释放以及这些过程的动态的详细方面是监管的，但是仍未抵消。进行分子动力学（MD）模拟，具有和不具有肽底物AAPV的PL646的模拟和MetadyAdnamics模拟，以研究PL646对基底结合时的结构，分子运动和自由能景观（FEL）的变化。结果表明，在仿真期间，基板结合的PL646采用比无基质形式更稳定且紧凑的构象。然而，少数位于基板结合袋或连接到催化残余物的区域，显示出对基板结合时的柔韧性增加。组合的基本动态（ED）分析显示，在基板结合时，明显的位移不仅发生在基板结合袋/位点，而且在表面暴露的环中发生。提出了由大的齐齐通动动动动引起的动态凹穴与PL646的底物识别，结合，取向，催化和产品释放相关联。构造的纤维揭示了无基质PL646具有比与其基材复合物中的蛋白酶更坚固且更宽的自由能表面，以及较高的最小自由能水平，表明基板结合在增加稳定性的同时降低了构象灵活性PL646。本作工作中提出的结果将促进更好地理解角质层降解丝氨酸蛋白酶PL646的结构动态功能关系。

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  • 来源
    《RSC Advances》 |2017年第67期|共11页
  • 作者

    Yang Li-Quan; Sang Peng; Zhang Ruo-Peng; Liu Shu-Qun;

  • 作者单位

    Dali Univ Coll Agr &

    Biol Sci Dali Peoples R China;

    Dali Univ Coll Agr &

    Biol Sci Dali Peoples R China;

    Dali Univ Affiliated Hosp 1 Dept Reprod Med Dali Peoples R China;

    Yunnan Univ State Key Lab Conservat &

    Utilizat Bioresources Y Kunming Yunnan Peoples R China;

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