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

M R Gunner, Taichi Murakami, Ariën S. Rustenburg, Mehtap Işık, and John D. Chodera.
Journal of Computer Aided Molecular Design 34:561, 2020. [DOI] [PDF] [GitHub]

Here, we demonstrate how the physical nature of protonation and tautomeric state effects means that the standard state free energies of each microscopic protonation/tautomeric state at a single pH is sufficient to describe the complete pH-dependent microscopic and macroscopic populations. We introduce a new kind of diagram that uses this concept to illustrate a variety of pH-dependent phenomena, and show how it can be used to identify common issues with protonation state prediction algorithms. As a result, we recommend future blind prediction challenges utilize microstate free energies at a single reference pH as the minimal sufficient information for assessing prediction accuracy and utility.

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Intlekofer A, Wang B, Liu H, Shah H, Carmona-Fontaine C, Rustenburg AS, Salah S, Gunner MR, Chodera JD, Cross JR, and Thompson CB.
Nature Chemical Biology 13:494, 2017. [DOI] [PDF] [GitHub]

At low pH, metabolic enzymes lactate dehydrogenase and malate dehydrogenase undergo shifts in substrate utilization that have high relevance to cancer metabolism due to surprisingly simple protonation state effects.