Methyl-Induced Polarization Destabilizes the Noncovalent Interactions of N-Methylated Lysines.
Methyl-Induced Polarization Destabilizes the Noncovalent Interactions of N-Methylated Lysines.
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DOI：
10.1002/chem.202100644
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发表时间：
2021-07-26
影响因子：
4.3
通讯作者：
Varma, Sameer
中科院分区：
文献类型：
--
作者：
Rahman, Sanim;Wineman-Fisher, Vered;Nagy, Peter R.;Al-Hamdani, Yasmine;Tkatchenko, Alexandre;Varma, Sameer
关键词：
赖氨酸甲基化可以通过改变赖氨酸的疏水性以及其电子结构来修饰非共价相互作用。虽然前者的后果有文件记载，但后者的影响在很大程度上仍然未知。了解电子结构对于确定生物甲基化如何调节蛋白质-蛋白质结合以及人工甲基化如何影响甲基化赖氨酸用作光谱探针和蛋白质结晶促进剂的实验非常重要。在这里进行的基准第一性原理计算表明，甲基诱导的极化减弱了胺与蛋白质官能团的静电吸引力-盐桥，氢键和阳离子-π相互作用分别减弱了10.3，7.9和3.5 kT。多极分析表明，削弱静电是由于改变感应效应，克服增加吸引力从甲基增强极化率和分散。由于这些影响的基本性质，预计在许多情况下都会出现。对蛋白质结构中甲基化赖氨酸的调查揭示了几种情况，其中甲基诱导的极化是改变非共价相互作用的主要驱动因素，并且在这些情况下，发现不稳定在0.6-4.7 kT范围内。甲基诱导的极化在调节生物学功能中起主导作用的最清楚的情况是识别组蛋白上赖氨酸甲基化状态的PHD 1-PHD 2结构域。这些结果拓宽了我们对甲基化如何调节非共价相互作用的理解。铵甲基化减弱了其与蛋白质官能团的静电吸引力-盐桥，氢键和阳离子-π相互作用分别减弱了10.3，7.9和3.5 kT。减弱的静电是由于改变的感应效应，克服了甲基增强的极化率和分散增加的吸引力。由于这些影响的基本性质，预计在许多情况下都会出现。
Lysine methylation can modify non-covalent interactions by altering lysine’s hydrophobicity as well as its electronic structure. While ramifications of the former are documented, the effects of the latter remain largely unknown. Understanding electronic structure is important for determining how biological methylation modulates protein-protein binding, and how artificial methylation impacts experiments in which methylated lysines are used as spectroscopic probes and protein crystallization facilitators. Benchmarked first principles calculations undertaken here reveal that methyl-induced polarization weakens electrostatic attraction of amines with protein functional groups – salt bridges, hydrogen bonds and cation-π interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Multipole analysis shows that weakened electrostatics is due to altered inductive effects that overcome increased attraction from methyl-enhanced polarizability and dispersion. These effects, due to their fundamental nature, are expected to be present in many cases. Survey of methylated lysines in protein structures reveals several cases where methyl-induced polarization is the primary driver of altered non-covalent interactions, and in these cases, destabilizations are found to be in the 0.6–4.7 kT range. The clearest case of where methyl-induced polarization plays a dominant role in regulating biological function is that of the PHD1-PHD2 domain that recognizes lysine methylated-states on histones. These results broaden our understanding of how methylation modulates non-covalent interactions. Ammonium methylation weakens its electrostatic attraction with protein functional groups – salt bridges, hydrogen bonds and cation-π interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Weakened electrostatics is due to altered inductive effects that overcome increased attraction from methyl-enhanced polarizability and dispersion. These effects, due to their fundamental nature, are expected to be present in many cases.
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