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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics
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Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

机译：使用温度加速的分子动力学对蛋白质进行大规模构象采样

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摘要

We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t → r" transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 A, with a twist of 90° relative to the equatorial domain, and the root-mean-squared deviation relative to the r" conformer is reduced from 13 to 5 A, representing fairly high predictive capability. For gp120, the method predicts both counterro-tation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 A from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMO generates plausible all-atom models of the so-far structurally uncharacterized unli-ganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases.
机译：我们展示了如何在集合变量中应用温度加速分子动力学（TAMD）方法[Maragliano L，Vanden-Eijnden E（2006）Chem Phys Lett 426：168-175]来采样全域多域蛋白质的构象空间。原子，显式溶剂化的分子动力学模拟。该方法允许系统在物理温度下计算出的一组集体变量中，以超高温方式探索自由能表面。作为集合变量，我们选择连续子域中心的笛卡尔坐标。该方法适用于GroEL亚基，55 kDa，三结构域蛋白和HIV-1 gp120。对于GroEL，该方法诱导约40 ns的构象变化，概括了t→r“跃迁，并且未在未加速的分子动力学中观察到：顶端结构域错位30 A，相对于赤道结构域扭曲90°，相对于r“构象异构体的均方根偏差从13 A降低到5 A，代表了相当高的预测能力。对于gp120，该方法可以预测内部和外部域的反向旋转以及所谓的桥接片的破坏。尤其是，最初在CD4结合构象中的gp120上的TAMD访问与抗体F105配合物偏离gp120构象异构体3.6 A的构象，再次反映了良好的预测能力。 TAMO生成了迄今为止HIV-1 gp120的结构上未表征的未固定构象的合理的全原子模型，这可能被证明可用于开发抑制剂和免疫原。在两种情况下，所采用的虚拟温度也为构象异构体之间的自由能势垒提供了10 kcal / mol的粗略估计。

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