Computational prediction of heteromeric protein complex disassembly order using hybrid Monte Carlo/molecular dynamics simulation
Computational prediction of heteromeric protein complex disassembly order using hybrid Monte Carlo/molecular dynamics simulation
复制标题
使用混合蒙特卡罗/分子动力学模拟计算预测异聚蛋白复合物的分解顺序
DOI：
10.1039/d2cp00267a
复制
发表时间：
2022
影响因子：
3.3
通讯作者：
Tanaka Shigenori
中科院分区：
文献类型：
--
作者：
Kurisaki Ikuo;Tanaka Shigenori
细胞中包含生物现象的物理化学实体形成生化反应网络，并且这种网络的活性由多聚体蛋白质复合物调节。基于结构生物信息学技术的质谱（MS）实验和多聚体蛋白质对接模拟揭示了亚复合物在其结合形式下的分子水平化学计量和静态构型，从而揭示了亚复合物的种群和形成顺序。同时，这些方法并没有被设计成直接检查多聚体蛋白质组装和拆卸的时间动力学，理解蛋白质在生物环境中的功能表达机制的基本物理化学性质。为了解决这个问题，我们已经开发了一个原子模拟的混合蒙特卡罗/分子动力学（hMC/MD）方法的框架，并成功地观察到拆卸的血清淀粉样蛋白P组分蛋白的同聚五聚体在实验一致的顺序。在这项研究中，我们改进了hMC/MD方法来检查的色氨酸合成酶四聚体，在MS研究中的一个范例异聚体蛋白质复合物的拆卸过程。我们采用了基于似然性的选择方案，以确定在每个hMC/MD模拟周期的解离倾向的亚基对，并实现了高度可靠的预测的拆卸顺序没有先验知识的MS实验和结构生物信息学模拟。实验观察到的拆卸顺序的成功率超过0.9。我们同样成功地对其他三种四聚体蛋白质复合物进行了可靠的预测。这些成就表明，我们的hMC/MD方法作为一种通用的方法，以获得多聚体蛋白质复合物形成的微观和物理化学的见解的潜在适用性。
The physicochemical entities comprising the biological phenomena in the cell form a network of biochemical reactions and the activity of such a network is regulated by multimeric protein complexes. Mass spectroscopy (MS) experiments and multimeric protein docking simulations based on structural bioinformatics techniques have revealed the molecular-level stoichiometry and static configuration of subcomplexes in their bound forms, thus revealing the subcomplex population and formation orders. Meanwhile, these methodologies are not designed to straightforwardly examine the temporal dynamics of multimeric protein assembly and disassembly, essential physicochemical properties to understand the functional expression mechanisms of proteins in the biological environment. To address this problem, we have developed an atomistic simulation in the framework of the hybrid Monte Carlo/molecular dynamics (hMC/MD) method and succeeded in observing the disassembly of a homomeric pentamer of the serum amyloid P component protein in an experimentally consistent order. In this study, we improved the hMC/MD method to examine the disassembly processes of the tryptophan synthase tetramer, a paradigmatic heteromeric protein complex in MS studies. We employed the likelihood-based selection scheme to determine a dissociation-prone subunit pair at every hMC/MD simulation cycle and achieved highly reliable predictions of the disassembly orders without a priori knowledge of the MS experiments and structural bioinformatics simulations. The success rate for the experimentally-observed disassembly order is over 0.9. We similarly succeeded in reliable predictions for three other tetrameric protein complexes. These achievements indicate the potential applicability of our hMC/MD approach as a general-purpose methodology to obtain microscopic and physicochemical insights into multimeric protein complex formation.