Correlation between C═O Stretching Vibrational Frequency and p K a Shift of Carboxylic Acids.

Identifying the p K a values of aspartic acid (Asp) and glutamic acid (Glu) in active sites is essential for understanding enzyme reaction mechanisms. In this study, we investigated the correlation between the C═O stretching vibrational frequency (ν C═O ) of protonated carboxylic acids and the p K a values using density functional theory calculations. In unsaturated carboxylic acids (e.g., benzoic acid analogues), ν C═O decreases as the p K a increases (the negative correlation), whereas in saturated carboxylic acids (e.g., acetic acid analogues, Asp, and Glu), ν C═O increases as the p K a increases (the positive correlation) as long as the structure of the H-bond network around the acid is identical. The negative/positive correlation between ν C═O and p K a can be rationalized by the presence or absence of the C═C double bond. The p K a shift was estimated from the ν C═O shift of Asp and Glu in proteins on the basis of the negative correlation derived from benzoic acids. The previous estimations should be revisited by using the positive correlation derived in this study, as demonstrated by quantum mechanical/molecular mechanical calculations of ν C═O and electrostatic calculations of p K a on a key Asp85 in the proton-transfer pathway of bacteriorhodopsin.