Examining the assumptions underlying continuum-solvent models.
Examining the assumptions underlying continuum-solvent models.
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DOI：
10.1021/acs.jctc.5b00684
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发表时间：
2015-10-13
影响因子：
5.5
通讯作者：
Pettitt BM
中科院分区：
文献类型：
--
作者：
Harris RC;Pettitt BM
连续溶剂模型 (CSM) 已成功预测了许多量，包括小分子的无溶剂化能 (ΔG)，但它们并未始终成功地再现实验结合自由能 (ΔΔG)，特别是对于蛋白质-蛋白质复合物。一些 CSM 将 ΔG 分解为将不带电分子插入溶液中的自由能 (ΔGvdw) 和充电获得的自由能 (ΔGel)。有些人进一步将 ΔGvdw 分为将近乎坚硬的空腔插入溶液中的自由能 (ΔGrep) 和通过开启溶质与溶剂之间的色散相互作用而获得的自由能 (ΔGatt)。我们表明，对于 9 种蛋白质-蛋白质复合物，ΔGrep 和 ΔGvdw 在溶剂可及区域 A 中都不是线性的，正如许多 CSM 中所假设的那样，并且 ΔΔG 的相应成分在 A 的变化中不是线性的。我们表明，线性响应理论 (LRT) 对 ΔGatt 和 ΔΔGatt 产生了良好的估计，但从溶剂的初始或最终构型获得的 ΔΔGatt 估计与 LRT 的估计不一致。 LRT 对 ΔGel 的估计与显式溶剂模型 (ESM) 的预测相差超过 100 kcal/mol，并且对 ΔΔG 的相应成分 (ΔΔGel) 的估计相差超过 10 kcal/mol。最后，泊松-玻尔兹曼方程产生的 ΔGel 估计值与 ESM 的估计值相关，但其对 ΔΔGel 的估计值要小得多。这些发现可能有助于解释为什么许多 CSM 未能始终成功地预测许多复合物（包括蛋白质-蛋白质复合物）的 ΔΔG。
Continuum-solvent models (CSMs) have successfully predicted many quantities, including the solvation-free energies (ΔG) of small molecules, but they have not consistently succeeded at reproducing experimental binding free energies (ΔΔG), especially for protein–protein complexes. Several CSMs break ΔG into the free energy (ΔGvdw) of inserting an uncharged molecule into solution and the free energy (ΔGel) gained from charging. Some further divide ΔGvdw into the free energy (ΔGrep) of inserting a nearly hard cavity into solution and the free energy (ΔGatt) gained from turning on dispersive interactions between the solute and solvent. We show that for 9 protein–protein complexes neither ΔGrep nor ΔGvdw was linear in the solvent-accessible area A, as assumed in many CSMs, and the corresponding components of ΔΔG were not linear in changes in A. We show that linear response theory (LRT) yielded good estimates of ΔGatt and ΔΔGatt, but estimates of ΔΔGatt obtained from either the initial or final configurations of the solvent were not consistent with those from LRT. The LRT estimates of ΔGel differed by more than 100 kcal/mol from the explicit solvent model’s (ESM’s) predictions, and its estimates of the corresponding component (ΔΔGel) of ΔΔG differed by more than 10 kcal/mol. Finally, the Poisson–Boltzmann equation produced estimates of ΔGel that were correlated with those from the ESM, but its estimates of ΔΔGel were much less so. These findings may help explain why many CSMs have not been consistently successful at predicting ΔΔG for many complexes, including protein–protein complexes.