Converging free energy estimates: MM-PB(GB)SA studies on the protein-protein complex Ras-Raf
Converging free energy estimates: MM-PB(GB)SA studies on the protein-protein complex Ras-Raf
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DOI：
10.1022/jcc.10379
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发表时间：
2004-01-30
影响因子：
3
通讯作者：
Case, DA
中科院分区：
文献类型：
--
作者：
Gohlke, H;Case, DA
估计蛋白质-蛋白质相互作用能是当前模拟协议的一个非常具有挑战性的任务。在这里，绝对结合自由能报告的复杂的H-Ras/C-Raf 1使用MM-PB（GB）SA方法，测试的内部一致性和模型依赖性的结果。平均气相能量（MM），溶剂化自由能确定的广义玻恩模型（GB/SA），和熵的贡献计算的正常模式分析的快照从10 ns显式溶剂分子动力学的结果在高估的结合亲和力时，溶剂可及的表面积依赖的模型被用来估计非极性溶剂化的贡献。应用腔溶剂化自由能和明确建模的溶质-溶剂货车德瓦尔斯相互作用能的总和，而不是提供较少的负估计的非极性溶剂化的贡献。当极性对溶剂化自由能的贡献通过求解泊松-玻尔兹曼方程（PB）来确定时，计算的结合亲和力强烈依赖于所选择的原子半径集。对于三个GB模型的研究，不同的绝对偏差PB能量被发现为未结合的蛋白质和复合物。作为一种替代正常模式的计算，准谐波分析已进行估计熵的贡献，由于结合后的溶质的灵活性的变化。然而，这样的熵估计在10 ns的模拟时间之后不收敛，这表明采样问题可能限制这种方法的适用性。最后，结合自由能估计从快照的未结合的蛋白质提取的复杂的轨迹导致低估的结合亲和力。这表明，在将计算成本较低的“单轨迹替代方案”应用于可能因约束而在灵活性和结构方面发生重大变化的系统时，需要谨慎行事。Ras-Raf结合自由能的最佳估计值为-8.3 kcal mol（-1），与实验结果-9.6 kcal mol（-1）吻合较好，但还需要进一步探讨导致这一结果的应用方案的可转移性。(C)2003 Wiley Periodicals，Inc.
Estimating protein-protein interaction energies is a very challenging task for current simulation protocols. Here, absolute binding free energies are reported for the complex H-Ras/C-Raf1 using the MM-PB(GB)SA approach, testing the internal consistency and model dependence of the results. Averaging gas-phase energies (MM), solvation free energies as determined by Generalized Born models (GB/SA), and entropic contributions calculated by normal mode analysis for snapshots obtained from 10 ns explicit-solvent molecular dynamics in general results in an overestimation of the binding affinity when a solvent-accessible surface area-dependent model is used to estimate the nonpolar solvation contribution. Applying the sum of a cavity solvation free energy and explicitly modeled solute-solvent van der Waals interaction energies instead provides less negative estimates for the nonpolar solvation contribution. When the polar contribution to the solvation free energy is determined by solving the Poisson-Boltzmann equation (PB) instead, the calculated binding affinity strongly depends on the atomic radii set chosen. For three GB models investigated, different absolute deviations from PB energies were found for the unbound proteins and the complex. As an alternative to normal-mode calculations, quasiharmonic analyses have been performed to estimate entropic contributions due to changes of solute flexibility upon binding. However, such entropy estimates do not converge after 10 ns of simulation time, indicating that sampling issues may limit the applicability of this approach. Finally, binding free energies estimated from snapshots of the unbound proteins extracted from the complex trajectory result in an underestimate of binding affinity. This points to the need to exercise caution in applying the computationally cheaper "one-trajectory-alternative" to systems where there may be significant changes in flexibility and structure due to binding. The best estimate for the binding free energy of Ras-Raf obtained in this study of -8.3 kcal mol(-1) is in good agreement with the experimental result of -9.6 kcal mol(-1), however, further probing the transferability of the applied protocol that led to this result is necessary. (C) 2003 Wiley Periodicals, Inc.