Gautam Narayan, Chapagain Prem P, Adhikari Narayan P, Tiwari Purushottam B
Central Department of Physics, Tribhuvan University, Kirtipur, Kathmandu, Nepal.
Tri-Chandra Multiple Campus, Tribhuvan University, Ghantaghar, Kathmandu, Nepal.
J Biomol Struct Dyn. 2024 Dec 11:1-10. doi: 10.1080/07391102.2024.2437523.
Interactions of transcriptional corepressors such as histone deacetylase 7 (HDAC7), a class IIa HDAC, with myocyte enhancer factor-2 (MEF2) regulate MEF2 activity. Despite previous investigations exploring interactions between HDAC7 and MEF2, a detailed characterization of the HDAC7-MEF2 functional complex is still lacking. Herein, we first modeled the structure of the HDAC7-MEF2A complex and investigated the inter-protein interactions using all-atom molecular dynamics (MD) simulations. We identified specific amino acids within HDAC7 and MEF2A that participate in interactions such as salt bridges, hydrogen bonds, and hydrophobic interactions. Our results reveal a salt bridge formed between LYS96(HDAC7) and ASP63(MEF2A). Our analysis also predicted formations of reliable hydrogen bonds between SER82(HDAC7) and ASP63(MEF2A) as well as LYS96(HDAC7) and ASP63(MEF2A). In addition, clustering of hydrophobic residues at the interface contributes in stabilizing the HDAC7-MEF2A complex. Results from multiple sequence alignment show that most of the HDAC7 residues that are predicted to associate with MEF2A are conserved in at least three class IIa HDACs and all predicted residues in MEF2A are conserved in MEF2s. We also found that the association of DNA to MEF2A has no significant effect on HDAC7-MEF2A interactions. Our results may also provide useful insights into the interactions between other class IIa HDACs and MEF2s.
转录共抑制因子如IIa类组蛋白去乙酰化酶7（HDAC7）与肌细胞增强因子2（MEF2）的相互作用调节MEF2活性。尽管之前有研究探索HDAC7与MEF2之间的相互作用，但仍缺乏对HDAC7 - MEF2功能复合物的详细表征。在此，我们首先对HDAC7 - MEF2A复合物的结构进行建模，并使用全原子分子动力学（MD）模拟研究蛋白质间的相互作用。我们确定了HDAC7和MEF2A中参与盐桥、氢键和疏水相互作用等的特定氨基酸。我们的结果揭示了LYS96（HDAC7）和ASP63（MEF2A）之间形成的盐桥。我们的分析还预测了SER82（HDAC7）与ASP63（MEF2A）以及LYS96（HDAC7）与ASP63（MEF2A）之间可靠氢键的形成。此外，界面处疏水残基的聚集有助于稳定HDAC7 - MEF2A复合物。多序列比对结果表明，预测与MEF2A结合的大多数HDAC7残基在至少三种IIa类HDAC中保守，且MEF2A中所有预测残基在MEF2s中保守。我们还发现DNA与MEF2A的结合对HDAC7 - MEF2A相互作用没有显著影响。我们的结果也可能为其他IIa类HDAC与MEF2s之间的相互作用提供有用的见解。
