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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.

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    $\begingroup$ The pKas are not gas phase, they are in aqueous solution, but they are for the individual lipid, and predicted based on similar molecules. $\endgroup$ – Buck Thorn Mar 6 at 18:34
  • $\begingroup$ What kinds of lipids are we talking about here? The set of functional groups is pretty limited, and you can probably extract the pKa from the most significant functional group from an acidicity/basicity standpoint, at least to first order. $\endgroup$ – Zhe Mar 6 at 19:28
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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.
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