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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nucleotide-dependent conformational states of actin
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Nucleotide-dependent conformational states of actin

机译：肌动蛋白的核苷酸依赖性构象状态

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摘要

The influence of the state of the bound nucleotide (ATP, ADP-Pi, or ADP) on the conformational free-energy landscape of actin is investigated. Nucleotide-dependent folding of the DNase-l binding (DB) loop in monomeric actin and the actin trimer is carried out using all-atom molecular dynamics (MD) calculations accelerated with a multiscale implementation of the metadynamics algorithm. Additionally, an investigation of the opening and closing of the actin nucleotide binding cleft is performed. Nucleotide-dependent free-energy profiles for all of these conformational changes are calculated within the framework of metadynamics. We find that in ADP-bound monomer, the folded and unfolded states of the DB loop have similar relative free-energy. This result helps explain the experimental difficulty in obtaining an ordered crystal structure for this region of monomeric actin. However, we find that in the ADP-bound actin trimer, the folded DB loop is stable and in a free-energy minimum. It is also demonstrated that the nucleotide binding cleft favors a closed conformation for the bound nucleotide in the ATP and ADP-Pi states, whereas the ADP state favors an open confirmation, both in the monomer and trimer. These results suggest a mechanism of allosteric interactions between the nucleotide binding cleft and the DB loop. This behavior is confirmed by an additional simulation that shows the folding free-energy as a function of the nucleotide cleft width, which demonstrates that the barrier for folding changes significantly depending on the value of the cleft width.
机译：研究了结合核苷酸的状态（ATP，ADP-Pi或ADP）对肌动蛋白构象自由能态的影响。 DNase-1结合（DB）环在单体肌动蛋白和肌动蛋白三聚体中的核苷酸依赖性折叠是使用通过多尺度实现元动力学算法加速的全原子分子动力学（MD）计算来进行的。另外，进行肌动蛋白核苷酸结合裂隙的打开和闭合的研究。所有这些构象变化的依赖核苷酸的自由能谱在元动力学框架内计算。我们发现，在与ADP结合的单体中，DB环的折叠和未折叠状态具有相似的相对自由能。该结果有助于解释为单体肌动蛋白的该区域获得有序晶体结构的实验困难。但是，我们发现在结合ADP的肌动蛋白三聚体中，折叠的DB环稳定且自由能最小。还证明核苷酸结合裂隙有利于在ATP和ADP-Pi状态下结合核苷酸的闭合构象，而ADP状态有利于单体和三聚体中的开放确认。这些结果表明核苷酸结合裂隙和DB环之间的变构相互作用的机制。此行为通过其他模拟得到了证实，该模拟显示了折叠自由能随核苷酸裂缝宽度的变化而变化，这表明折叠障碍物的变化取决于裂缝宽度的值。

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    Jim Pfaendtner; Davide Branduardi; Michele Parrinello; Thomas D. Pollard; Gregory A. Voth;

  • 作者单位

    Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850 Computational Science, Department of Chemistry and Applied Biosciences, Eidgenoessische Technische Hochschule (ETH) Zurich, Universita delta Svizzera italiana Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland;

    Computational Science, Department of Chemistry and Applied Biosciences, Eidgenoessische Technische Hochschule (ETH) Zurich, Universita delta Svizzera italiana Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland;

    Computational Science, Department of Chemistry and Applied Biosciences, Eidgenoessische Technische Hochschule (ETH) Zurich, Universita delta Svizzera italiana Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland;

    Departments of Molecular Cellular and Developmental Biology, Cell Biology and Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8103;

    Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cytoskeleton; DNase binding loop; filament; protein folding;

    机译：细胞骨架DNase结合环;灯丝;蛋白质折叠;

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