## Saturday, May 13, 2017

### Computing apparent pKa values using QM energies of isodesmic reactions

A few days ago I presented some preliminary pKa results.  Almost all the molecules in the set have more than one ionisable group. Here's how I compute the apparent pKa values

The microscopic pKa values are computed by
\begin{equation}
\label{eqn:pka}
\mathrm{pK_a}=\mathrm{pK_a^{ref}} + \frac{\Delta G^\circ}{RT\ln (10)}
\end{equation}
where $\Delta G^\circ$ denotes the change in standard free energy for the isodesmic reaction
\begin{equation}
\mathrm{ BH^+ + B_{ref} \rightleftharpoons B + B_{ref}H^+ }
\end{equation}
If there are more than one titrateable sites then several protonation states can contribute to the apparent pKa.  Here I follow the approach described by Bochevarov et al. If $\mathrm{D}$ and $\mathrm{P}$ differ by one proton and there are $M$ deprotonated sites and $N$ protonated sites then
\begin{equation}
\mathrm{K_{app}}  = \frac{([\mathrm{D}_1] + [\mathrm{D}_2] + ... [\mathrm{D}_M])[\mathrm{H}^+]}{[\mathrm{P}_1] + [\mathrm{P}_2] + ... [\mathrm{P}_N]}
\end{equation}
which can be rewritten in terms of microscopic pKa values
\begin{equation}
\mathrm{K_{app}}  = \sum^M_j \frac{1}{\sum^N_i 10^{pK_{ij}} }
\end{equation}
The sum contains contains microscopic pKa values for which more than one protonation state is changed. For example, molecule with three ionizable groups $(\mathrm{B_1H^+B_2H^+B_3H^+})$ will have the following microscopic pKa value
\begin{equation}
\label{eqn:pkapp}
K_{ij} = \frac{ [\mathrm{B_1B_2H^+B_3][H^+]}}{[\mathrm{B_1H^+B_2B_3H^+}]}
\end{equation}
in the expression for the apparent pKa value for going from the doubly to the singly protonated state. However, the error in such a pKa value is considerably higher due to less error cancellation and such pKa values are therefore neglected in the sum.

In the Bochevarov et al. implementation the user defines the titrateable group for which the apparent pKa is computed.  However, in my approach all possible protonation states so the assignment of the apparent pKa value to a particular ionizable group is not immediately obvious.  Inspection of Eq $\ref{eqn:pkapp}$ shows that the largest microscopic pKa values will dominate the sum over $N$, while the smallest of these maximum pKa values will dominate the sum over $M$. Thus, the apparent pKa is assigned to the functional group corresponding to the microscopic pKa
\begin{equation}
\label{eqn:max}
pK^\prime_{ij} = \min_{j}(\{ \max_{i}(\{ pK_{ij} \} ) \} )
\end{equation}
In some cases there are several microscopic pKa that contribute almost equally to the respective sums and for these cases the apparent pKa value cannot meaningfully be assigned to a single ionizable sites.  In my approach include all microscopic pKa values that are within 0.6 pKa units of the respective maximum and minimum values defined in Eq $\ref{eqn:max}$.   I choose 0.6 because that is the site-site interaction energy below which two groups titrate simultaneously.

You can find the code I wrote to do this here. It is not cleaned up yet. 