Enhanced HP1α homodimer interaction via force-induced salt bridge formation: implications for chromatin crosslinking and phase separation†

Shingo Tsukamoto, Mohammad Khavani, Nya Domkam and Mohammad R. K. Mofrad
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Abstract

Recent studies have underscored the potential role of Heterochromatin Protein 1α (HP1α) in chromatin crosslinking, phase separation, and the orchestration of nuclear mechanics. One of the cornerstones of HP1α functionality lies in its homodimerization through the chromoshadow domain (CSD), which is crucial for these processes. Nevertheless, it has remained unknown how HP1α can foster condensations responding to mechanical force and induce phase separation in the mechanically unfavorable heterochromatin region. To elucidate the biophysical basis of HP1α, we used full atomistic molecular dynamics (MD) simulations, focusing on the CSD–CSD dimer of HP1α under a pulling force. Notably, force application resulted in a stronger, more stable interaction at the α-helix interface of the CSD–CSD. This enhanced interaction was attributed to a force-induced salt bridge formation on the α-helix interface, emerging from an angle alteration of a lysine residue that enables closer proximity to a glutamic acid residue on the paired CSD. This study reveals an intriguing facet of HP1α mechanics: its mechanical sensitivity, wherein dimerization strength is enhanced by mechanical force. The molecular dynamics of the CSD–CSD dimer under force provide novel insights into HP1α mechanics, contributing to our understanding of chromatin mechanics and phase separation.

Abstract Image

通过力诱导盐桥形成增强HP1α同源二聚体相互作用:对染色质交联和相分离的影响†
最近的研究强调了异染色质蛋白 1α(HP1α)在染色质交联、相分离和核机械协调中的潜在作用。HP1α 功能的基石之一是通过染色质阴影结构域(CSD)进行同源二聚化,这对这些过程至关重要。然而,HP1α如何在机械不利的异染色质区域促进对机械力做出反应的凝集并诱导相分离仍是未知数。为了阐明HP1α的生物物理基础,我们使用了全原子分子动力学(MD)模拟,重点研究了在拉力作用下HP1α的CSD-CSD二聚体。值得注意的是,施力后,CSD-CSD 的 α 螺旋界面产生了更强、更稳定的相互作用。这种相互作用的增强归因于α-螺旋界面上由外力诱导形成的盐桥,该盐桥是由赖氨酸残基的角度变化引起的,它使配对 CSD 上的谷氨酸残基更加接近。这项研究揭示了 HP1α 力学的一个有趣方面:它的机械敏感性,即二聚化强度会因机械力而增强。CSD-CSD 二聚体在作用力下的分子动力学提供了对 HP1α 力学的新见解,有助于我们理解染色质力学和相分离。
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