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：
10.1002/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目前模拟协议中一个非常具有挑战性的任务。本文采用MM-PB(GB)SA方法报道了配合物H-Ras/C-Raf1的绝对束缚自由能，检验了结果的内部一致性和模型依赖性。平均气相能（MM），由广义波恩模型（GB/SA）确定的溶剂化自由能，以及通过正常模式分析从10 ns显式溶剂分子动力学中获得的快照计算的熵贡献，通常导致当使用溶剂可及表面积依赖模型来估计非极性溶剂化贡献时，对结合亲和力的估计过高。应用空腔溶剂化自由能和明确建模的溶质-溶剂范德华相互作用能的总和，可以为非极性溶剂化贡献提供较少的负估计。当通过求解泊松-玻尔兹曼方程（PB）来确定极性对溶剂化自由能的贡献时，计算出的结合亲和力强烈依赖于所选择的原子半径集。对于所研究的三种GB模型，发现未结合蛋白和复合物与PB能量的绝对偏差不同。作为正态计算的一种替代方法，准谐波分析已被用于估计溶质弹性在结合时的变化所引起的熵贡献。然而，这种熵估计在10 ns的模拟时间后不会收敛，这表明采样问题可能会限制这种方法的适用性。最后，根据从复杂轨迹中提取的未结合蛋白质的快照估计的结合自由能导致低估了结合亲和力。这表明，在将计算成本更低的“单轨迹替代方案”应用于可能因绑定而导致灵活性和结构发生重大变化的系统时，需要谨慎行事。本研究得到的Ras-Raf结合自由能的最佳估计为-8.3 kcal mol(-1)，与实验结果-9.6 kcal mol（-1）很吻合，但是，进一步探讨导致这一结果的应用方案的可转移性是必要的。(C) 2003 Wiley期刊有限公司
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.