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Using Atomic Charges to Describe the p K a of Carboxylic Acids

Abstract : In this study, we present an accurate protocol for the fast prediction of pK a 's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental pK a values. Five charge descriptors, three charge models, three solvent models, gas phase calculations, several DFT methods (combination of eight DFT functionals and fifteen basis sets) and four different semiempirical approaches were tested. Among those, the best combination to reproduce experimental pK a 's is to compute NPA atomic charge using the SMD model at the M06L/6-311G(d,p) level of theory and selecting the maximum atomic charge on the carboxylic oxygen atoms (R 2 = 0.955). The applicability of the suggested protocol and its stability along geometrical changes are verified by molecular dynamics simulations performed for a set of aspartate, glutamate and alanine peptides. By reporting the calculated atomic charge of the carboxylate form into the linear relationship derived in this work, it should be possible to estimate accurately the amino acid's pK a 's in protein environment.
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Contributor : Gérald Monard <>
Submitted on : Thursday, June 17, 2021 - 1:34:44 PM
Last modification on : Saturday, June 19, 2021 - 3:38:41 AM
Long-term archiving on: : Saturday, September 18, 2021 - 6:32:26 PM


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Zeynep Pinar Haslak, Sabrina Zareb, Ilknur Dogan, Viktorya Aviyente, Gérald Monard. Using Atomic Charges to Describe the p K a of Carboxylic Acids. Journal of Chemical Information and Modeling, American Chemical Society, 2021, ⟨10.1021/acs.jcim.1c00059⟩. ⟨hal-03263534⟩



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