Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics
Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics
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DOI：
10.1073/pnas.0914540107
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发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Vanden-Eijnden, Eric
中科院分区：
文献类型：
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作者：
Abrams, Cameron F.;Vanden-Eijnden, Eric
我们展示了如何在集体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] 在全原子、显式溶剂化分子动力学模拟中对多域蛋白质的构象空间进行采样。该方法允许系统在物理温度下计算的一组集体变量中超高温地探索自由能表面。作为集体变量，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（一种 55 kDa、三结构域蛋白）和 HIV-1 gp120。对于 GroEL，该方法在大约 40 ns 内诱导构象变化，再现 t -> r '' 转变，并且在未加速的分子动力学中未观察到：顶端域位移 30 埃，相对于赤道域扭转 90 埃，相对于 r '' 构象异构体的均方根偏差从 13 埃减少到 5 埃，代表相当高的预测 能力。对于 gp120，该方法预测内部和外部域的反向旋转以及所谓的桥接片的破坏。特别是，gp120上的TAMD最初处于CD4结合构象，访问与抗体F105复合物中的gp120构象异构体偏离3.6埃的构象，再次反映了良好的预测能力。 TAMD 生成了迄今为止结构上尚未表征的 HIV-1 gp120 的无配体构象的合理全原子模型，这可能在抑制剂和免疫原的开发中有用。在这两种情况下，所采用的虚构温度还粗略估计了构象异构体之间的自由能垒为 10 kcal/mol。
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 angstrom, 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 angstrom, representing fairly high predictive capability. For gp120, the method predicts both counterrotation 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 angstrom from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded 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.