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J Comput Aided Mol Des. 2020 Feb 12. doi: 10.1007/s10822-020-00280-7. [Epub ahead of print]

Standard state free energies, not pKas, are ideal for describing small molecule protonation and tautomeric states.

Author information

1
Department of Physics City College of New York, New York, NY, 10031, USA. mguner@ccny.cuny.edu.
2
Department of Physics City College of New York, New York, NY, 10031, USA.
3
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
4
Graduate Program in Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY, 10065, USA.
5
Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY, 10065, USA.
6
Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, 10065, USA.

Abstract

The pKa is the standard measure used to describe the aqueous proton affinity of a compound, indicating the proton concentration (pH) at which two protonation states (e.g. A- and AH) have equal free energy. However, compounds can have additional protonation states (e.g. AH2+), and may assume multiple tautomeric forms, with the protons in different positions (microstates). Macroscopic pKas give the pH where the molecule changes its total number of protons, while microscopic pKas identify the tautomeric states involved. As tautomers have the same number of protons, the free energy difference between them and their relative probability is pH independent so there is no pKa connecting them. The question arises: What is the best way to describe protonation equilibria of a complex molecule in any pH range? Knowing the number of protons and the relative free energy of all microstates at a single pH, ∆G°, provides all the information needed to determine the free energy, and thus the probability of each microstate at each pH. Microstate probabilities as a function of pH generate titration curves that highlight the low energy, observable microstates, which can then be compared with experiment. A network description connecting microstates as nodes makes it straightforward to test thermodynamic consistency of microstate free energies. The utility of this analysis is illustrated by a description of one molecule from the SAMPL6 Blind pKa Prediction Challenge. Analysis of microstate ∆G°s also makes a more compact way to archive and compare the pH dependent behavior of compounds with multiple protonatable sites.

KEYWORDS:

Multiprotic; Protonation state; SAMPL6; Tautomer; pH titration; pKa

PMID:
32052350
DOI:
10.1007/s10822-020-00280-7

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