Biological and Biochemical Foundations

In a folded protein, a glutamate side chain has a pKapK_a of 7.2, substantially higher than its value in aqueous solution. Which feature of the side chain's microenvironment most likely causes this shift?

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Answer: C (Burial of the glutamate side chain in a nonpolar pocket lacking a compensating charge)

Protonated glutamate is neutral, whereas deprotonated glutamate carries a negative charge. Burial in a nonpolar pocket lacking a compensating charge destabilizes the deprotonated form relative to the protonated form. Consequently, a higher pH is required for deprotonation, increasing the side chain's pKapK_a. An ion pair with arginine or a hydrogen bond that stabilizes the deprotonated carboxylate would instead lower the pKapK_a.

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