Computational Prediction of Association Free Energies for the C 3 d - CR 2 Complex and Comparison to Experimental Data

The complement system functions to clear pathogenic threats from the body and is part of the innate immune system. The association between complement protein C3d and B or T cell-receptor CR2 (complement receptor 2) represents a crucial link between innate and adaptive immunities. The goal of this study is to computationally predict association abilities of C3d and CR2 mutants by theoretically calculating electrostatic free energies of association with and without solvation effects. We demonstrate that incorporation of solvation effects is necessary to accurately predict 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. Additionally, an inversely proportional relationship is demonstrated between the calculated solvation free energy differences and previously calculated ionization free energy differences. Our results yield new insights into the physicochemical properties underlying C3d-CR2 association. Moreover, our results can also be extended to any complex with excessively charged components. This is a basic study, aimed toward understanding the theoretical basis of immune system regulation at the molecular level, which can be the groundwork for the design of regulators with tailored properties, vaccines, and biotechnology products in general. F A C U L T Y m e n T o R Dimitrios Morikis Department of Bioengineering Alexander joined my lab during his freshman year, being very enthusiastic and ambitious about doing research. During his first two years, he matured as a researcher by learning about research methodology, biomolecular modeling and simulation, and immune system function and regulation. As a Junior, with all the core requirements in mathematics, physics, chemistry, and biology, he was ready to undertake a project of higher challenge. He did so with great success as indicated by the current publication. Alexander used a computational protocol implemented by graduate student Jianfeng Yang, ’07, and modified by graduate student Chris Kieslich, both coauthors in this paper, to construct a number of theoretical mutants and to predict the association abilities for an immune system protein and its receptor. He performed a meticulous analysis of his data in view of previous experimental work and theoretical calculations. This type of work is important for the design of immune system therapeutics. Alexander has the ability to process large amounts of complex information. Although he is a quiet participant in a typical research discussion, he comes back to our next meeting with data from well-planned and well-executed calculations and with impeccable presentations. Alexander S. Cheung, Dimitrios Morikis Graduate Student Assistants: Jianfeng Yang, Chris A. Kieslich Department of Bioengineering University of California, Riverside Computational Prediction of Association Free Energies for the C3d-CR2 Complex and Comparison to Experimental Data