TY - JOUR
T1 - Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis
T2 - a molecular dynamics study
AU - Ramya Chandar Charles, M.
AU - Hsieh, Hsing Pang
AU - Selvaraj Coumar, Mohane
N1 - Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/7/3
Y1 - 2019/7/3
N2 - 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. Communicated by Ramaswamy H. Sarma.
AB - 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. Communicated by Ramaswamy H. Sarma.
UR - http://www.scopus.com/inward/record.url?scp=85054873345&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054873345&partnerID=8YFLogxK
U2 - 10.1080/07391102.2018.1491422
DO - 10.1080/07391102.2018.1491422
M3 - Article
C2 - 30047835
AN - SCOPUS:85054873345
VL - 37
SP - 2581
EP - 2592
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
SN - 0739-1102
IS - 10
ER -