Thermodynamics and Free Energy Landscape of BAR-Domain Dimerization from Molecular Simulations.
Thermodynamics and Free Energy Landscape of BAR-Domain Dimerization from Molecular Simulations.
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DOI：
10.1021/acs.jpcb.0c10992
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发表时间：
2021-04-22
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影响因子：
--
通讯作者：
Johnson ME
中科院分区：
文献类型：
--
作者：
Jhaveri A;Maisuria D;Varga M;Mohammadyani D;Johnson ME
具有 BAR 结构域的蛋白质具有结合和重塑生物膜的功能，其中 BAR 结构域的二聚化是该功能的关键步骤。这些结构域可以在溶液中或定位到膜表面后二聚化。在这里，我们使用分子动力学 (MD) 模拟来表征溶液中 LSP1 BAR 结构域蛋白之间同二聚化的结合热力学。通过将 MARTINI 粗粒度蛋白质模型与元动力学增强采样相结合，我们构建了一个二维自由能表面，将结合与非结合系综量化为两个距离变量的函数。通过这种方法，我们的模拟可以同时表征一系列采样二聚体的结构和相对稳定性，描绘出异质且极其稳定的结合整体，其中适当的晶体结构二聚体在 100 mM NaCl 溶液中最稳定。采样的非特异性二聚体涉及与 LSP1 BAR 结构域形成的高阶寡聚体的实验结构一致的接触。由于 BAR 二聚体和寡聚体可以在膜上组装，因此我们表征了已知膜结合斑块的相对排列，发现只有特定的二聚体排列才能与膜形成强相互作用。因此，我们预测在膜上结合或组装时对特定二聚体的强烈选择。当蛋白质形成稳定的寡聚体时，建立同二聚体接触的成对稳定性在实验上很困难，但通过这里使用的方法，我们可以分离这些接触，为研究膜上相同的相互作用提供基础。
Proteins with BAR domains function to bind to and remodel biological membranes, where the dimerization of BAR domains is a key step in this function. These domains can dimerize in solution or after localizing to the membrane surface. Here, we characterize the binding thermodynamics of homodimerization between the LSP1 BAR domain proteins in solution, using molecular dynamics (MD) simulations. By combining the MARTINI coarse-grained protein models with enhanced sampling through metadynamics, we construct a two-dimensional free energy surface quantifying the bound versus unbound ensembles as a function of two distance variables. With this methodology, our simulations can simultaneously characterize the structures and relative stabilities of a range of sampled dimers, portraying a heterogeneous and extraordinarily stable bound ensemble, where the proper crystal structure dimer is the most stable in a 100 mM NaCl solution. Nonspecific dimers that are sampled involve contacts that are consistent with experimental structures of higher-order oligomers formed by the LSP1 BAR domain. Because the BAR dimers and oligomers can assemble on membranes, we characterize the relative alignment of the known membrane binding patches, finding that only the specific dimer is aligned to form strong interactions with the membrane. Hence, we would predict a strong selection of the specific dimer in binding to or assembling when on the membrane. Establishing the pairwise stabilities of homodimer contacts is difficult experimentally when the proteins form stable oligomers, but through the method used here, we can isolate these contacts, providing a foundation to study the same interactions on the membrane.
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