Binding of Proteins to Copolymers of Varying Charges and Hydrophobicity: A Molecular Mechanism and Computational Strategies
Binding of Proteins to Copolymers of Varying Charges and Hydrophobicity: A Molecular Mechanism and Computational Strategies
复制标题
蛋白质与不同电荷和疏水性的共聚物的结合：分子机制和计算策略
DOI：
10.1021/acs.biomac.2c00521
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发表时间：
2022
影响因子：
6.2
通讯作者：
Yongqin Lv
中科院分区：
文献类型：
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作者：
Xiao Xu;Tong Zhang;Stefano Angioletti-Uberti;Yongqin Lv
由于其选择性结合靶蛋白的能力，共聚物纳米颗粒（NPs）含有疏水性和带电基团的选择组合，经常被报道为有效的抗体样类似物。然而，由于共聚物NP在其随机单体序列和交联共聚物基体方面的内在无序性，共聚物NP确实与折叠良好的蛋白质抗体有显著不同，共聚物NP与靶蛋白之间的络合可能不是由于锁键式的相互作用，而是由于一种新的未被探索的分子机制。在这里，我们使用隐式水显式粗粒度（CG）分子动力学（MD）模拟和生物层干涉（BLI）分析研究了一种关键的生物标记蛋白，vimentin，与一组随机共聚物链相互作用。由于vimentin二聚体（VD）表面的电荷和疏水性各向异性，发现了一组键合共聚物在VD上的不均匀吸附，不同的结合位点具有能量不均一性和吸附中的协同效应。增加共聚物的电荷或疏水性可能会对吸附产生不同的影响。在本研究中，我们发现随着共聚物电荷的增加，低疏水性共聚物的蛋白质覆盖率增加，高疏水性共聚物的蛋白质覆盖率降低，这可以解释为在负载这些共聚物时VD上各种功能斑块的分布和大小。采用覆盖相关的Langmuir模型，我们提出了一种模拟协议，通过拟合模拟的结合等温线来解决共聚物结合自由能的完整剖面。所得结果与BLI实验结果吻合较好，说明该方法对合理设计具有工程蛋白结合亲和力的共聚物NP具有重要意义。
Because of their ability to selectively bind to a target protein, copolymer nanoparticles (NPs) containing a selected combination of hydrophobic and charged groups have been frequently reported as potent antibody-like analogues. However, due to the intrinsic disorder of the copolymer NP in terms of its random monomer sequence and the cross-linked copolymer matrix, the copolymer NP is indeed strikingly different from a well-folded protein antibody and the complexation between the copolymer NP and a target protein is likely not due to a lock-key type of interaction but possibly due to a novel and unexplored molecular mechanism. Here, we study a key biomarker protein, vimentin, interacting with a set of random copolymer chains using implicit-water explicit-ion coarse-grained (CG) molecular dynamics (MD) simulations along with biolayer interferometry (BLI) analysis. Due to the charge and hydrophobicity anisotropy on the vimentin dimer (VD) surface, a set of bound copolymers are found inhomogenously adsorbed on the VD, with energetic heterogeneity for different binding sites and cooperative effect in the adsorption. Increasing the charge or hydrophobicity of the copolymer may have different consequences on the adsorption. In this study, we found that with more copolymer charges, the protein coverage increases for copolymers of low hydrophobicity and decreases of high hydrophobicity, which is explained by the distribution and size of various functional patches on the VD in loading those copolymers. Employing a coverage-dependent Langmuir model, we propose a simulation protocol to address the full profile of the copolymer binding free energy through the fit to the simulated binding isotherm. The obtained results correlate well with those from the BLI experiment, indicating the significance of this method for the rational design of the copolymer NP with engineered protein binding affinity.