Department of Bioengineering, Marmara University, Göztepe, Istanbul, Turkey.
Department of Genetics and Bioengineering, Istanbul Okan University, Tuzla, Istanbul, Turkey.
J Comput Aided Mol Des. 2020 Sep;34(9):965-974. doi: 10.1007/s10822-020-00316-y. Epub 2020 May 19.
CREB-binding protein (CBP) is a multi-subunit scaffold protein complex in transcription regulation process, binding and interacting with ligands such as mixed-lineage leukemia (MLL) and c-Myb allosterically. Here in this study, we have revisited the concept of allostery in CBP via residue-based interaction energy calculation based on molecular dynamics (MD) simulations. To this end, we conducted MD simulations of KIX:MLL:c-Myb ternary complex, its binary components and kinase-inducible domain (KID) interacting domain (KIX) backbone. Interaction energy profiles and cross correlation analysis were performed and the results indicated that KIX:MLL and KIX:c-Myb:MLL complexes demonstrate significant similarities according to both analysis methods. Two regions in the KIX backbone were apparent from the interaction energy and cross correlation maps that hold a key to allostery phenomena observed in CBP. While one of these regions are related to the ligand binding residues, the other comprises of L-G loop and α helix regions that have been found to have a significant role in allosteric signal propagation. All in all, residue-based interaction energy calculation method is demonstrated to be a valuable calculation technique for the detection of allosteric signal propagation and ligand interaction regions.
CREB 结合蛋白（CBP）是转录调控过程中的多亚基支架蛋白复合物，通过变构与混合谱系白血病（MLL）和 c-Myb 等配体结合和相互作用。在本研究中，我们通过基于分子动力学（MD）模拟的残基相互作用能计算重新审视了 CBP 中的变构概念。为此，我们对 KIX:MLL:c-Myb 三元复合物、其二元组件和激酶诱导结构域（KID）相互作用结构域（KIX）骨架进行了 MD 模拟。进行了相互作用能谱和互相关分析，结果表明，根据这两种分析方法，KIX:MLL 和 KIX:c-Myb:MLL 复合物表现出显著的相似性。在 KIX 骨架的互相关图和相互作用能图谱中，有两个区域明显与变构现象有关，这些区域与配体结合残基有关，另一个区域包含 L-G 环和α螺旋区域，这些区域在变构信号传递中起着重要作用。总之，基于残基的相互作用能计算方法被证明是一种有价值的计算技术，可用于检测变构信号传递和配体相互作用区域。
