Histone deacetylases (HDACs) regulate a variety of cellular processes such as cell differentiation, proliferation, and apoptosis. Interaction of HDAC3 with HDAC4 has association with HDAC4 enzymatic activity. SMRT, HDAC3 activating cofactor, mediates the HDAC3-HDAC4 interactions. The intermolecular complex involving HDAC3 and HDAC4 remains poorly investigated. Herein, we investigated HDAC3-HDAC4 molecular interactions both in the presence and absence of SMRT using all-atom molecular dynamics (MD) simulations to characterize the complex formations. We first modeled the HDAC3-HDAC4 and HDAC3-SMART-HDAC4 complexes and performed MD simulations of these complexes. Using simulation trajectories of MD simulations of both complexes, we explored key amino acid residues that are responsible to establish specific interactions across the binding interface. We also quantified the binding interactions via determinations MM/GBSA binding free-energies.
Gautam et al. (Sun,) studied this question.