Exploring protein native states and large-scale conformational changes with a modified generalized born model
Exploring protein native states and large-scale conformational changes with a modified generalized born model
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DOI：
10.1002/prot.20033
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发表时间：
2004-05-01
影响因子：
2.9
通讯作者：
Case, DA
中科院分区：
文献类型：
--
作者：
Onufriev, A;Bashford, D;Case, DA
隐式溶剂化模型为许多应用提供了一种相当准确且计算有效的方法来描述水溶剂化的静电。在这里，对流行的分析广义玻恩（GB）溶剂化模型进行了修改，以提高其计算大规模构象转变（例如蛋白质折叠）中自由能变化的溶剂极化部分的准确性。与早期的 GB 模型（在 AMBER-6 程序中实现）相比，改进版本相对于有限差分 Poisson-Boltzmann 连续体处理并没有过度稳定原生结构。除了改善折叠和展开构象异构体之间的能量平衡外，该算法（在 AMBER-7 和 NAB 分子建模软件包中提供）在硫氧还蛋白、蛋白 A 和泛素的超过 50 ns 的原生态分子动力学 (MD) 模拟以及 Barnase/Barstar 复合物形成的模拟中表现良好。对于硫氧还蛋白，已经探索了输入参数的各种组合，例如潜在的气相力场和原子半径。最佳性能是通过先前提出的对 Amber ff99 力场中扭转势的修改实现的，这为所有测试的蛋白质产生了稳定的天然轨迹，在 6 ns 的模拟时间后，与天然结构的主干均方根偏差类似于 1.5 埃。 Barnase/Barstar 复合物的结构从未结合状态开始再生，相对于复合物晶体结构的误差在 1.9 A 以内。 (C) 2004 Wiley-Liss, Inc.
Implicit solvation models provide, for many applications, a reasonably accurate and computationally effective way to describe the electrostatics of aqueous solvation. Here, a popular analytical Generalized Born (GB) solvation model is modified to improve its accuracy in calculating the solvent polarization part of free energy changes in large-scale conformational transitions, such as protein folding. In contrast to an earlier GB model (implemented in the AMBER-6 program), the improved version does not overstabilize the native structures relative to the finite-difference Poisson-Boltzmann continuum treatment. In addition to improving the energy balance between folded and unfolded conformers, the algorithm (available in the AMBER-7 and NAB molecular modeling packages) is shown to perform well in more than 50 ns of native-state molecular dynamics (MD) simulations of thioredoxin, protein-A, and ubiquitin, as well as in a simulation of Barnase/Barstar complex formation. For thioredoxin, various combinations of input parameters have been explored, such as the underlying gas-phase force fields and the atomic radii. The best performance is achieved with a previously proposed modification to the torsional potential in the Amber ff99 force field, which yields stable native trajectories for all of the tested proteins, with backbone root-mean-square deviations from the native structures being similar to 1.5 Angstrom after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 A relative to the crystal structure of the complex. (C) 2004 Wiley-Liss, Inc.