bioRxiv2022
N-terminal acetyltransferases (NATs) are overexpressed in various cancers. Specifically in lung cancer, human N--acetyltransferase D (hNatD) is upregulated and prevents the histone H4 N-terminal serine phosphorylation, leading to the epithelial-to-mesenchymal transition (EMT) of cancer cells. hNatD facilitates histone H4 N--terminal serine acetylation and halts the CK2-mediated serine phosphorylation. In the present study, we report the effects of four N-terminal mutant (S1C, R3C, G4D and G4S) histone H4 peptides on their bindings with hNatD by employing a molecular dynamics simulation. We also used graph theory-based analyses to understand residue correlation and communication in hNatD under the influence of WT and MT H4 peptides. Results show that S1C, R3C and G4S mutant peptides have significant stability at the catalytic site of hNatD. However, S1C, G4D and G4S peptides disrupt hNatD structure. Additionally, intramolecular hydrogen bond analysis reveals greater stability of hNatD in complex with R3C peptide. Further, intermolecular hydrogen bond analysis of acetyl-CoA with hNatD and its RMSD analysis in five complexes indicate that cofactor has greater stability in WT and R3C complexes. Our findings support previously reported experimental study on impacts of H4 mutations on its hNatD-mediated acetylation catalytic efficiency. The betweenness centrality (BC) analysis further gives insight into the hNatD residue communication dynamics that can be exploited to target hNatD using existed or novel drug candidates therapeutically. SECONDARY ABSTRACTMany N-terminal acetyltransferases (NATs) enzymes play important role in post-translational modification of histone tails. Research showed that these enzymes have been reported upregulated in many cancers. NatD is known to acetylate H4/H2A at the N-terminal. During lung cancer, this enzyme competes with the protein kinase CK2 and block the phosphorylation of H4 and, acetylates. Also, we observed that H4 has various mutations at the N-terminal and we considered only four mutations (S1C, R3C, G4D and G4S) to study the impacts of these mutations on H4 binding with NatD using MD simulation. Our results show that R3C stabilizes the NatD whereas remaining mutations destabilize the NatD. Thus, mutations have significant impacts on NatD structure. Our finding supports previous analysis also. SIGNIFICANCEOur main objective in this study was to understand the structural and dynamics of hNatD under the influence of WT and MT H4 histones bindings. Previous experimental study reported that mutations on H4 N-terminus reduce the catalytic efficiency of N-Terminal acetylation. But here, we performed molecular-level study thus, we can understand how these mutations (S1C, R3C, G4D and G4S) cause significant depletion in catalytic efficiency of hNatD. Another, interesting observation is that enzymatic activity of hNatD is altered due to the considerably large deviation of acetyl-CoA from its original position (G4D). Further, simulation and correlation data suggest which regions of the hNatD are highly flexible and rigid and, which domains or residues have the correlation and anticorrelation. As hNatD is overexpressed in lung cancer, it is an important drug target for the cancer hence, our study provides structural information to target hNatD.