蛋白茶多酚复合物的分子模拟和小角X光散射研究

Protein and polyphenol both are important biopolymers to our body. Their complex attracted intensive interests in recent years due to the versatile bioactivities, such as antioxidant, anticarcinogenic, anti-aging and anti-inflammatory etc. This application will utilize an interdisciplinary approach including Monte Carlo (MC) simulation, Molecular Dynamic (MD) simulation, small X-ray scattering (SAXS) and bioinformatics methods to address some critical problems associated with the complex made of protein (including hemoglobin and serum albumin) and tea polyphenol. The following key issues will be investigated: i) to construct the coarse grained model, the atomic model and their corresponding force fields, then intergrate them in the MC and the MD simulations of the protein - tea polyphenol complex; ii) to identify the critical binding sites in proteins, determine the binding affinity, trace the conformation variation of proteins upon the binding of tea polyphenols and the aggregation of proteins induced by the bridging-effect of tea polyphenol; iii) to present the mechanism for the formation and aggregation of the protein - tea polyphenol complex,the dispersion of the complex and complex aggregates and their stimuli responsibility to the change of chemical structures of tea polyphenols, stoichiometry and ionic strengths; iv) to collect SAXS data from the corresponding protein - tea polyphenol systems engaged in molecular simulations, assess and optimize the force field so to provide consistent scattering patterns from both molecular simulations and SAXS; v) to test the robustness of the optimized force field in the molecular simulation of protein - tea polyphenols complex with different chemical structures of tea polyphenols, stoichiometry and ionic strengths, then try to generalize its application to other similar protein complex; vi) finally, to clarify whether hemoglobin and serum albumin are cooperatively or competitively interact with tea polyphenols, provide a clear molecular view for the bioactivity of the protein - tea polyphenol complex. Such knowledge will lead to a better understanding of some health benificial bioactivities from natural polymers and facilitate bioactive polymers based functional material development.

借助Monte Carlo (MC)和Molecular Dynamics (MD)分子模拟方法、小角X光散射(SAXS)结合生物信息学等多学科交叉方法，建立血清蛋白、血红蛋白与茶多酚的粗粒化模型、全原子模型及其对应的能量势场；研究蛋白质与茶多酚相互作用形成复合物过程中的关键结合位点、结合强度、蛋白结构变化和茶多酚桥连作用下的大分子聚集行为；明晰蛋白茶多酚复合物的作用机制、分散模式以及对诸如不同茶多酚的化学计量、化学结构和体系的离子强度等环境变量的响应性；将蛋白茶多酚复合物及其聚集体结构的模拟结果与从相应复合物体系利用SAXS获得的散射图案进行比较，定量评估并优化分子模拟的能量势场，以期推广该研究方法到其它类似蛋白质复合物体系的研究；考察血清蛋白、血红蛋白与茶多酚的竞争或协同作用模式，为理解蛋白茶多酚复合物参与的重要生物物理过程提供清晰的科学阐述。

通过对分子对接、蒙特卡洛和分子动力学模拟方法、小角X光散射和大数据方法的融合发展，围绕含蛋白质复合物和高分子复杂体系结构的定量解析，开发出了一套具有特色的多学科交叉、理论计算模拟与实验有机结合的研究方法。利用该方法，系统深入地研究了血清蛋白、胰蛋白酶、酪蛋白酶、泛素、细胞色素C等多个功能蛋白与含茶多酚及其它生物活性小分子复合物的结构、相互作用和结构-活性关系。将小角X光散射携带的结构信息引入杂化的分子模拟中，有效地提高了蛋白质结构模拟靠近目标态的收敛和增强抽样；在此基础上，明确了几种蛋白质解折叠机理以及小分子协同作用下的热力学和动力学演变规律；通过量子化学-分子力场计算与分子对接、分子动力学模拟和自由能计算在蛋白质复合物结构中的耦合，剖析了多个蛋白质-小分子复合物的结构演化特征，明确了复合物生成过程中的竞争和协同作用模式，为高通量药物设计和药物筛选提供了可靠的实例；进一步发展该方法并与信息学相结合，建立了围绕复杂体系结构的定量研究方法，该研究路线能够有力地推进分子层面上的作用机制剖析，提高了药物分子理性设计的可靠性。资助期间发表含Macromolecules, J. Membr. Sci., Adv. Colloid Interface Sci., J. Phys. Chem. B等论文14篇,国际国内会议口头报告11次。