蛋白质在PEG聚合物刷表面吸附行为的全原子模拟研究

Understanding the mechanism of the selective adsorption of protein on the surface coated by polymer brushes made of poly (ethylene glycol) (PEG) is significantly important for the development of biomaterials with good biocompatibility. The key issue in the mechanism is how the adsorbed behaviors of protein are dominated by the synergetic effect of the conformations of polymer in the brush, the characteristics of protein and the redistribution of solvent. In this project, the chain length and density of PEG are used to build typically structured brushes, and polymer chains in the brush cover isolate, contact and overlap states in good, theta and poor solvents. Scaling relationships accounting kinetic parameters including the orientation and relaxation of proteins, the synergetic change of polymer conformations and the diffusion of solvents, as well as thermodynamic parameters such as the B-factor of protein and the size of polymer against normalized variables in specific states will be explored. Through the broad sampling, optimal orientations near PEG brushes can be determined in a reference to the internal polar coordinates of protein. Meanwhile, the potential of mean force, the evaluation of the contributions from entropy and elementary physical interactions will be presented. Then different proteins with typical sizes, shapes, and distributions of surface charge, etc., in the adsorption to PEG brushes will be investigated. Finally, classic models about protein adsorption into polymer brushes will be revisited and molecular mechanism for the studied systems will be presented. The consensus and the characteristics of the adsorption of different proteins into different structured polymer brushes will be provided for further development in adjusting the adsorption of proteins with polymer brushes.

建立蛋白质在聚乙二醇（PEG）聚合物刷表面的选择性吸附机理对开发良好生物相容性的材料具有重要的指导意义。其中，聚合物刷构象、蛋白质特性和溶液环境三者如何协同作用调控蛋白质吸附行为是亟待明确的问题。利用全原子分子动力学模拟研究几种典型蛋白质在不同构象聚合物刷表面的吸附行为，通过PEG链长和链密度构建具有代表性的聚合物刷构象，使PEG链历经孤立、接触和交叠三种状态，分析蛋白质构象和取向弛豫、吸附时间等动力学指标，探索结构涨落、链尺寸等热力学参数的特征标度关系；明确不同蛋白质的优势吸附取向，绘制蛋白质在聚合刷表面吸附的能量势貌图，并考察熵、焓和基本相互作用的贡献；跟踪蛋白质和聚合物刷构象及水分子分布的协同变化；阐述具有不同尺寸、形状和表面电荷等特性的蛋白质在聚合物刷表面的选择性吸附行为，明晰PEG聚合物刷选择性阻抗蛋白质吸附的机理，为优化设计聚合物刷并实现对蛋白质吸附行为的有效调控提供指导。

该项目执行期间，首先，我们成功的开发了更为合理和真实的全原子和粗粒化聚合反应模型。利用全原子聚合反应模型构建了聚酰胺膜的微观结构，发现了水分子在聚酰胺膜网络结构中的非正常动力学行为，明晰了水分子通过小步连续扩散和跳跃扩散传输机制。借助于粗粒化聚合反应模型，研究了表面与自由引发剂共存下的聚合物链生长的主控因素和在A/B二组分溶液中共聚反应诱导的高分子聚集的程。其次，整合量子化学、分子对接、分子动力学和自由能计算方法，开发了高通量预测药物小分子与靶蛋白相互作用机制及药物分子活性的计算平台，利用其明晰了超氧化物歧化酶、醛糖还原酶、酪氨酸酶等多个靶蛋白与含黄酮分子及其他生物活性小分子的复合物结构，解析了多种药物分子抑制靶蛋白的分子机理，建立了定量的药物分子结构-活性关系模型。第三方面，将小角X光散射携带的结构信息引入杂化的蒙特卡洛-分子动力学模拟（MC-MD）方法中，增强了蛋白构象的抽样效率，明晰了几种蛋白质解折叠过程及机理。最后，利用量子化学方法，阐明了取代基团位置对环辛烯开环聚合反应位置及立体选择性的影响规律。本项目中多尺度的模拟研究可为实验上设计高性能聚酰胺反渗透膜、新型功能性聚合物纳米复合材料，高活性药物分子及具有立体选择性的开环聚合单体提供可靠的理论指导。资助期间已发表含Anal. Chem., Macromolecules, J. Chem. Inf. Model, Phys. Chem. Chem. Phys., Plos one等论文13篇。