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DFT Estimation of pKb Values – New Paper in JCIM


As a continuation of our previous work on estimating pKa values from DFT calculations for carboxylic acids, we now present the complementary pKb values for amino groups by the same method, and the coupling of both methodologies for predicting the isoelectric point -pI- values of amino acids as a proof of concept.

Analogously to our work on pKa, we now used the Minimum Surface Electrostatic Potentia, VS,min, as a descriptor of the availability of Nitrogen’s lone pair and correlated it with the experimental basicity of a large number of amines, separated into three groups: primary, secondary and tertiary amines.

Interestingly, the correlation coefficient between experimental and calculated pKb values decreases in the following order: primary (R2 = 0.9519) > secondary (R2 = 0.9112) > tertiary (R2 = 0.8172). This could be due to steric effects, the change in s-character of the lone pair or just plain old selection bias. Nevertheless, there is a good correlation between both values and the resulting equations can predict the pKb value of an amino group within less of a unit, which is very good for a statistical method that does not require the calculation of a full thermodynamic cycle.

We then took thirteen amino acids (those without titratable side chains) and calculated simultaneously VS,min and VS,max for the amino and the carboxyl group (this latter with the use of equation 2 from our previous work published in Molecules MDPI) and the arithmetical average of both gave us their corresponding pI values with an agreement of less than one unit.

This work is now available at the Journal of Chemical Information and Modeling (DOI: 10.1021/acs.jcim.9b01173); as always a shoutout is due to the people working on it: Leonardo “Leo” Lugo, Gustavo “Gus” Mondragón and leading the charge Dr. Jacinto Sandoval-Lira.

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