Mapping the Interactions Among Class IIa Histone Deacetylases and Myocyte Enhancer Factor 2s.

Myocyte enhancer factor 2 (MEF2) transcription factors regulate several developmental programs, including the control of neural crest development and neuronal differentiation as well as survival. MEF2s are highly expressed in cerebellar granule neurons. Class IIa histone deacetylases (HDACs), abundantly expressed in the brain as well, repress gene expression activity of MEF2 via physical interactions and play a critical role in neuronal apoptosis. In this work, we conducted molecular dynamics (MD) simulation-based investigations to investigate interactions among different class IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) and MEF2s (MEF2A, MEF2B, MEF2C, and MEF2D). Our results show that hydrophobic interactions are the main mechanism for the formation of class IIa HDAC-MEF2 complexes. Our analysis shows that L66 and L67 in all MEF2s mostly contribute to the hydrophobic interactions. All residues that establish hydrophobic interactions, hydrogen bonding, and salt bridges are conserved in all MEF2s. Calculations of the MM/GBSA binding free energies also show that the class IIa HDAC-MEF2 complexes exhibit comparable binding affinities. We performed surface plasmon resonance (SPR)-based direct binding experiments using four different purified class IIa HDACs and MEF2A to validate our computational investigations. The SPR results confirmed the direct binding between the class IIa HDACs and MEF2A with fairly comparable nanomolar affinity (3.5 nM to 19.1 nM). This is a comprehensive study to map interactions among class IIa HDACs and MEF2s. We believe that our investigation offers the scientific community valuable insights to further understand, explore, and investigate biomolecular systems that include the class IIa HDAC-MEF2 complex formations.