Gautam Narayan, Wang Sophia, Üren Aykut, Chapagain Prem P, Adhikari Narayan P, Tiwari Purushottam B
Central Department of Physics, Tribhuvan University, Kirtipur, Kathmandu 44613, Nepal.
Tri-Chandra Multiple Campus, Tribhuvan University, Ghantaghar, Kathmandu 44613, Nepal.
J Chem Inf Model. 2025 Jun 23;65(12):6249-6260. doi: 10.1021/acs.jcim.5c00858. Epub 2025 Jun 6.
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.
肌细胞增强因子2（MEF2）转录因子调控多种发育程序，包括对神经嵴发育、神经元分化以及存活的控制。MEF2在小脑颗粒神经元中高度表达。IIa类组蛋白去乙酰化酶（HDAC）在大脑中也大量表达，通过物理相互作用抑制MEF2的基因表达活性，并在神经元凋亡中起关键作用。在这项工作中，我们基于分子动力学（MD）模拟进行了研究，以探究不同的IIa类HDAC（HDAC4、HDAC5、HDAC7和HDAC9）与MEF2（MEF2A、MEF2B、MEF2C和MEF2D）之间的相互作用。我们的结果表明，疏水相互作用是IIa类HDAC-MEF2复合物形成的主要机制。我们的分析表明，所有MEF2中的L66和L67主要促成疏水相互作用。所有建立疏水相互作用、氢键和盐桥的残基在所有MEF2中都是保守的。MM/GBSA结合自由能的计算还表明，IIa类HDAC-MEF2复合物表现出相当的结合亲和力。我们使用四种不同纯化的IIa类HDAC和MEF2A进行了基于表面等离子体共振（SPR）的直接结合实验，以验证我们的计算研究。SPR结果证实了IIa类HDAC与MEF2A之间的直接结合，具有相当的纳摩尔亲和力（3.5 nM至19.1 nM）。这是一项全面的研究，用于绘制IIa类HDAC与MEF2之间的相互作用图谱。我们相信，我们的研究为科学界提供了有价值的见解，以进一步理解、探索和研究包括IIa类HDAC-MEF2复合物形成的生物分子系统。
