Department of Bioengineering, University of California, Riverside, CA 92521.
Biopolymers. 2010 Jun;93(6):509-19. doi: 10.1002/bip.21388.
The complement system is an integral part of the innate immune system that participates in the clearance of pathogens from the body. The association between complement protein fragment C3d and B or T cell-receptor complement receptor (CR) 2 represents a crucial link between innate and adaptive immunities. The goal of this study is to predict association abilities of C3d and CR2 mutants by theoretically calculating electrostatic free energies of association and to assess the importance of solvation effects in the calculations. We demonstrate that calculated solvation free energy differences and Coulombic free energies of association are more sensitive than electrostatic free energies of association in solution and, thus, more accurate in predicting previously published experimental data for the association abilities (relative to the parent proteins) of specific C3d and CR2 mutants. We show that a proportional relationship exists between the predicted solvation free energy differences and the experimental data, while an inversely proportional relationship exists between the predicted Coulombic free energies of association and the experimental data. Our results yield new insights into the physicochemical properties underlying C3d-CR2 association. We discuss the predictive validity of Coulombic, solvation, and solution electrostatic free energies of association and the generalization of our method for theoretical mutagenesis studies of other systems. This is a basic study, aimed toward improving our understanding of the theoretical basis of immune system regulation at the molecular level. Such insight can serve as the groundwork for the design of regulators with tailored properties, vaccines, and other biotechnology products.
补体系统是先天免疫系统的一个组成部分，参与清除体内的病原体。补体蛋白片段 C3d 与 B 或 T 细胞受体补体受体 (CR) 2 的关联代表了先天免疫和适应性免疫之间的关键联系。本研究的目的是通过理论计算结合的静电自由能来预测 C3d 和 CR2 突变体的结合能力，并评估计算中溶剂化效应的重要性。我们证明，与结合的静电自由能相比，计算得出的溶剂化自由能差异和库仑结合能在溶液中更敏感，因此更能准确预测之前发表的关于特定 C3d 和 CR2 突变体的结合能力（相对于亲本蛋白）的实验数据。我们表明，预测的溶剂化自由能差异与实验数据之间存在比例关系，而预测的库仑结合能与实验数据之间存在反比关系。我们的结果为 C3d-CR2 结合的物理化学性质提供了新的见解。我们讨论了库仑、溶剂化和溶液静电结合能的预测有效性，以及我们的方法在其他系统的理论诱变研究中的推广。这是一项基础研究，旨在提高我们对分子水平免疫系统调节的理论基础的理解。这种见解可以为具有定制特性的调节剂、疫苗和其他生物技术产品的设计提供基础。
