Calculate pKa for lipids

Question

I would like to calculate $\mathrm{p}K_\mathrm{a}$ of lipid molecules using some software tools. I have tried ChemAxon and compared with ChemDraw professional 16.0 version they are mostly similar. I think both are in gaseous phase.

Do I have any chance to calculate the $\mathrm{p}K_\mathrm{a}$'s in aqueous phase using solvent parameters? Any software tool suggestion are highly appreciated.

Answer 1

See H++ if you want a rough prediction of $\mathrm{p}K_\mathrm{a}$.

If you want to more accurately calculate the $\mathrm{p}K_\mathrm{a}$ of your molecules, you should run a quantum mechanics calculation with a continuum solvent model (example calculation: [1]).

The general outline is as follows. Run a geometry optimization and vibrational mode analysis on your system in basic and conjugate acidic forms. So, $\ce{BH+}$ and $\ce{B}$, or $\ce{BH}$ and $\ce{B-}$, depending on what your system looks like. This will allow you to extract a free energy of reaction for each of your lipid molecules.

Importantly, these calculations will not give accurate single point free energies, but the relative values ($∆G$) will be. As such, you will need a reference $∆G$ from literature of a similar reaction to "set the 0" of your values. Finally, you can get $\mathrm{p}K_\mathrm{a}$ from $∆G$ using

$$\mathrm{p}K_\mathrm{a} = \frac{∆G^\circ}{2.303RT}$$

Refrences

1. Liptak, M. D.; Shields, G. C. Accurate $\mathrm{p}K_\mathrm{a}$ Calculations for Carboxylic Acids Using Complete Basis Set and Gaussian-n Models Combined with CPCM Continuum Solvation Methods. Journal of the American Chemical Society 2001, 123 (30), 7314–7319. https://doi.org/10.1021/ja010534f.