Mono- and di-methylation of the H3K9 residue in the histone tail by G9a lysine methyltransferase is associated with transcriptional suppression of genes. Here, we use molecular dynamics simulation and free energy calculations of five different modified/mutated G9a substrate peptides to elucidate the rationale behind the substrate binding to G9a. We also investigated the binding energy contribution based architecture of the active site of G9a to understand substrate and inhibitor binding. Wild type peptide (H3K9) shows better binding affinity than mono- and di-methylated lysine (K9) and other modified peptides (K9A and R8A). Arg8 of the substrate peptide is crucial for determining the degree of conformational freedom/stability of the wild type substrate peptide, as well as binding to G9a. Our results also suggest that the G9a active site is segregated into energy rich and low regions, and the energy rich region alone is used by the inhibitors for binding. These insights into the active site architecture should be taken into consideration in virtual screening experiments designed to discover novel inhibitors for G9a. In particular, compounds that could interact with the six residues of G9a - Asp1074, Asp1083, Leu1086, Asp1088, Tyr1154 and Phe1158 - should be preferentially tested in G9a inhibition biological assays.
Date:
2019-07-03
Relation:
Journal of Biomolecular Structure and Dynamics. 2019 Jul 3;37(10):2581-2592.
