Department of Chemical and Biological Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4961-6. doi: 10.1073/pnas.0914540107. Epub 2010 Mar 1.
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 degrees 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 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 A 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.
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]，以便在全原子、显式溶剂化的分子动力学模拟中对多域蛋白质的构象空间进行采样。该方法允许系统在一组在物理温度下计算的集体变量中高温探索自由能表面。作为集体变量，我们选择了连续亚域中心的笛卡尔坐标。该方法应用于 GroEL 亚基，一种 55kDa 的三域蛋白质和 HIV-1 gp120。对于 GroEL，该方法在大约 40ns 内诱导了构象变化，这些变化再现了 t --> r('') 转变，并且在非加速分子动力学中观察不到：顶端域相对于赤道域位移 30A，扭转 90 度，相对于 r('')构象的均方根偏差从 13 减少到 5A，这代表了相当高的预测能力。对于 gp120，该方法预测了内域和外域的反向旋转以及所谓的桥接片的破坏。特别是，TAMD 最初在与 CD4 结合的构象下对 gp120 进行预测，会访问与与抗体 F105 结合的 gp120 构象偏差 3.6A 的构象，这再次反映了良好的预测能力。TAMD 生成了 HIV-1 gp120 迄今为止结构未表征的无配体构象的合理全原子模型，这可能对抑制剂和免疫原的开发有用。所采用的虚构温度还粗略估计了两种情况下构象之间的自由能势垒为 10kcal/mol。
