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

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.