Why do histone monomethylation and dimethylation cause a significant difference in binding to LEDGF?

Abstract

Lens epithelium-derived growth factor (LEDGF) is a chromatin-binding protein. It regulates gene transcription and is associated with acquired immunodeficiency syndrome and cancer. Its PWWP domain binds to histone H3 at K36 (H3K36). The binding affinity depends on H3K36 methylation. To investigate this dependency, we performed molecular dynamics simulations of the PWWP domain and histone fragments. We found that not only hydrophobic interaction but also electrostatic interaction is important. The binding is not maintained with nonmethylated and monomethylated H3K36 because the tips of these H3K36s form hydrogen bonds with water molecules, while dimethylated and trimethylated H3K36 form no such hydrogen bond, making this binding stable.