Predictive QM/MM Modeling of Modulations in Protein-Protein Binding by Lysine Methylation.
Predictive QM/MM Modeling of Modulations in Protein-Protein Binding by Lysine Methylation.
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赖氨酸甲基化对蛋白质结合调节的预测QM/MM模型。
DOI：
10.1016/j.jmb.2020.166745
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发表时间：
2021-02-05
影响因子：
5.6
通讯作者：
Varma, Sameer
中科院分区：
文献类型：
--
作者：
Rahman, Sanim;Wineman-Fisher, Vered;Al-Hamdani, Yasmine;Tkatchenko, Alexandre;Varma, Sameer
赖氨酸甲基化是蛋白质-蛋白质结合的关键调节因子。赖氨酸的氨基可以接受最多三个甲基，实验表明蛋白质-蛋白质结合自由能对甲基化程度很敏感。根据甲基赖氨酸结合域结合口袋中存在的化学和结构特征，这些敏感性已经合理化。然而，理解他们的具体作用需要进行积极的分析。在这里，我们提出了一个结合量子力学和分子力学方法的理论框架，并计算了甲基化对蛋白质-蛋白质结合自由能的影响。这种方法的优点是，它直接从自洽电子密度获得甲基化对诱导、极化率和色散的所有局部非平凡效应的贡献，同时使用计算高效的经典平均场方法确定充分描述的水化效应的贡献。讨论了这种方法的局限性，我们注意到16种情况中有14种预测的自由能与实验相符。对这些案例的关键评估导致了以下主要原则，这些原则推动了蛋白质结构域对甲基化状态的识别。甲基化通常会减少蛋白质之间的成对相互作用。这使结合偏向甲基化程度较低的状态。然而，与此同时，甲基化也使蛋白质更容易部分脱水，并将它们置于蛋白质-蛋白质复合体中。后一种效应使结合偏向于更高的甲基化状态。甲基化对蛋白质-蛋白质结合的整体影响最终取决于这两种影响之间的平衡，据观察，这是通过几种局部特征的组合来调节的。
Lysine methylation is a key regulator of protein-protein binding. The amine group of lysine can accept up to three methyl groups, and experiments show that protein-protein binding free energies are sensitive to the extent of methylation. These sensitivities have been rationalized in terms of chemical and structural features present in the binding pockets of methyllysine binding domains. However, understanding their specific roles requires an energetic analysis. Here we propose a theoretical framework to combine quantum and molecular mechanics methods, and compute the effect of methylation on protein-protein binding free energies. The advantages of this approach are that it derives contributions from all local non-trivial effects of methylation on induction, polarizability and dispersion directly from self-consistent electron densities, and at the same time determines contributions from well-characterized hydration effects using a computationally efficient classical mean field method. Limitations of the approach are discussed, and we note that predicted free energies of fourteen out of the sixteen cases agree with experiment. Critical assessment of these cases leads to the following overarching principles that drive methylation-state recognition by protein domains. Methylation typically reduces the pairwise interaction between proteins. This biases binding toward lower methylated states. Simultaneously, however, methylation also makes it easier to partially dehydrate proteins and place them in protein-protein complexes. This latter effect biases binding in favor of higher methylated states. The overall effect of methylation on protein-protein binding depends ultimately on the balance between these two effects, which is observed to be tuned via several combinations of local features.
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蛋白质甲基转移酶和去甲基酶抑制剂。
影响因子：
62.1
作者：
Kaniskan HÜ;Martini ML;Jin J
通讯作者：
Jin J
影响因子：
16.8
作者：
Iwase, Shigeki;Xiang, Bin;Ghosh, Sharmistha;Ren, Ting;Lewis, Peter W.;Cochrane, Jesse C.;Allis, C. David;Picketts, David J.;Patel, Dinshaw J.;Li, Haitao;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
4.8
作者：
Horowitz, Scott;Yesselman, Joseph D.;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.
影响因子：
16.8
作者：
Cui, Gaofeng;Park, Sungman;Badeaux, Aimee I.;Kim, Donghwa;Lee, Joseph;Thompson, James R.;Yan, Fei;Kaneko, Satoshi;Yuan, Zengqiang;Botuyan, Maria Victoria;Bedford, Mark T.;Cheng, Jin Q.;Mer, Georges
通讯作者：
Mer, Georges
影响因子：
16.8
作者：
Collins, Robert E.;Northrop, Jeffrey P.;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong