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A Comprehensive Calorimetric Investigation of an Entropically Driven T Cell Receptor-Peptide/Major Histocompatibility Complex Interaction

Kathryn M. Armstrong ^* and Brian M. Baker ^* 

^* Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana 46556

Correspondence: Address reprint requests to Brian M. Baker, Tel.: 574-631-9810; Fax: 574-631-6652; E-mail: bbaker2{at}nd.edu.

The ß T cell receptor (TCR) is responsible for recognizing peptides bound and "presented" by major histocompatibility complex (MHC) molecules. We recently reported that at 25°C the A6 TCR, which recognizes the Tax peptide presented by the class I MHC human leukocyte antigen-A*0201 (HLA-A2), binds with a weak H°, a favorable S°, and a moderately negative C_p. These observations were of interest given the unfavorable binding entropies and large heat capacity changes measured for many other TCR-ligand interactions, suggested to result from TCR conformational changes occurring upon binding. Here, we further investigated the A6-Tax/HLA-A2 interaction using titration calorimetry. We found that binding results in a pK_a shift, complicating interpretation of measured binding thermodynamics. To better characterize the interaction, we measured binding as a function of pH, temperature, and buffer ionization enthalpy. A global analysis of the resulting data allowed determination of both the intrinsic binding thermodynamics separated from the influence of protonation as well as the thermodynamics associated with the pK_a shift. Our results indicate that intrinsically, A6 binds Tax/HLA-A2 with a very weak H°, an even more favorable S° than previously thought, and a relatively large negative C_p. Comparison of these energetics with the makeup of the protein-protein interface suggests that conformational adjustments are required for binding, but these are more likely to be structural shifts, rather than disorder-to-order transitions. The thermodynamics of the pK_a shift suggest protonation may be linked to an additional process such as ion binding.

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