On Computing Equilibrium Binding Constants for Protein–Protein Association in Membranes
On Computing Equilibrium Binding Constants for Protein–Protein Association in Membranes
复制标题
计算膜中蛋白质-蛋白质缔合的平衡结合常数
DOI：
10.1021/acs.jctc.2c00106
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
Straub, John E.
中科院分区：
文献类型：
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作者：
Majumder, Ayan;Kwon, Seulki;Straub, John E.
脂膜中的蛋白质缔合是膜蛋白功能的基础，具有重要的生物医学相关性。全原子和粗粒度模型已广泛用于理解膜中蛋白质-蛋白质相互作用并计算平衡关联常数。然而，膜中蛋白质的缓慢平移和旋转扩散对定义有助于缔合平衡和二聚化自由能的自由和结合态整体的构象的有效采样提出了挑战。我们重新审视血型糖蛋白 A TM 区域的同二聚化平衡。构象采样是使用沿着先前提出的一维集体变量的伞形采样进行的，并与使用 MARTINI v2.2 力场在二维集体变量空间上进行的采样进行比较。我们证明，一维集体变量受到天然同二聚体构象的限制采样的影响，导致自由能景观出现偏差。相反，沿着二维集体变量的模拟有效地表征了有助于关联平衡的热力学相关的本机和非本机相互作用。这些结果证明了当多个姿势对结合态整体有贡献时，准确表征结合平衡所面临的挑战。
Protein association in lipid membranes is fundamental to membrane protein function and of great biomedical relevance. All-atom and coarse-grained models have been extensively used to understand the protein–protein interactions in the membrane and to compute equilibrium association constants. However, slow translational and rotational diffusion of protein in membrane presents challenges to the effective sampling of conformations defining the ensembles of free and bound states contributing to the association equilibrium and the free energy of dimerization. We revisit the homodimerization equilibrium of the TM region of glycophorin A. Conformational sampling is performed using umbrella sampling along previously proposed one-dimensional collective variables and compared with sampling over a two-dimensional collective variable space using the MARTINI v2.2 force field. We demonstrate that the one-dimensional collective variables suffer from restricted sampling of the native homodimer conformations leading to a biased free energy landscape. Conversely, simulations along the two-dimensional collective variable effectively characterize the thermodynamically relevant native and non-native interactions contributing to the association equilibrium. These results demonstrate the challenges associated with accurately characterizing binding equilibria when multiple poses contribute to the bound state ensemble.