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Residues flanking the ARKme3T/S motif allow binding of diverse targets to the HP1 chromodomain: Insights from molecular dynamics simulations
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-10-24 , DOI: 10.1016/j.bbagen.2020.129771
Pavlína Pokorná , Miroslav Krepl , Jiří Šponer

Background

The chromodomain (CD) of HP1 proteins is an established H3K9me3 reader that also binds H1, EHMT2 and H3K23 lysine-methylated targets. Structural experiments have provided atomistic pictures of its recognition of the conserved ARKme3S/T motif, but structural dynamics' contribution to the recognition may have been masked by ensemble averaging.

Methods

We acquired ~350 μs of explicit solvent molecular dynamics (MD) simulations of the CD domain interacting with several peptides using the latest AMBER force fields.

Results

The simulations reproduced the experimentally observed static binding patterns well but also revealed visible structural dynamics at the interfaces. While the buried K0me3 and A−2 target residues are tightly bound, several flanking sidechains sample diverse sites on the CD surface. Different amino acid positions of the targets can substitute for each other by forming mutually replaceable interactions with CD, thereby explaining the lack of strict requirement for cationic H3 target residues at the −3 position. The Q−4 residue of H3 targets further stabilizes the binding. The recognition pattern of the H3K23 ATKme3A motif, for which no structure is available, is predicted.

Conclusions

The CD reads a longer target segment than previously thought, ranging from positions −7 to +3. The CD anionic clamp can be neutralized not only by the −3 and −1 residues, but also by −7, −6, −5 and +3 residues.

General Significance

Structural dynamics, not immediately apparent from the structural data, contribute to molecular recognition between the HP1 CD domain and its targets. Mutual replaceability of target residues increases target sequence flexibility.



中文翻译:

位于ARK me3 T / S基序侧翼的残基允许将各种靶标结合到HP1色域上:分子动力学模拟的见解

背景

HP1蛋白的色域(CD)是已建立的H3K9 me3读码器,还可以结合H1,EHMT2和H3K23赖氨酸甲基化的靶标。结构实验提供了其对保守的ARK me3 S / T基序的识别的原子图片,但是结构动力学对识别的贡献可能被整体平均掩盖了。

方法

我们使用最新的AMBER力场获得了约350μs的CD域与几种肽相互作用的显式溶剂分子动力学(MD)模拟。

结果

模拟很好地重现了实验观察到的静态结合模式,但也揭示了界面处可见的结构动力学。尽管掩埋的K 0 me3和A -2目标残基紧密结合,但几个侧翼侧链对CD表面的不同位点进行采样。靶标的不同氨基酸位置可以通过与CD形成相互可替换的相互作用而彼此替代,从而解释了对-3位阳离子H3靶标残基的严格要求。H3靶的Q -4残基进一步稳定结合。预测了H3K23 ATK me3 A主题的识别模式,该主题没有可用的结构。

结论

CD读取的目标段比以前想象的要长,范围从-7到+3。CD阴离子钳位不仅可以被-3和-1残基中和,还可以被-7,-6,-5和+3残基中和。

一般意义

从结构数据中无法立即看出的结构动力学有助于HP1 CD域与其靶标之间的分子识别。靶残基的相互替换增加了靶序列的灵活性。

更新日期:2020-11-03
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