The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular
proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of
the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been
most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation
and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive.
Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential
mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not
available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the
molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic
(MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/
AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD
simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in
binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general
base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was
employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in
acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may
provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the
discovery of regulators against GCN5 enzymes and related HAT family enzymes.