We're working on pKa prediction using semiempirical methods and need to compute pKa values for molecules with several ionizable groups. Here are my current thoughts so far.
Background: one ionizable group
If there is only one tritrateable site
$$ \mathrm{BH \rightleftharpoons B + H^+} \ \ \ K=\mathrm{\frac{[B][H^+]}{[BH]}} $$
then the fraction of $\mathrm{BH}$ molecules $f_{\mathrm{BH}}$ is $$
\begin{split}
f_{\mathrm{BH}} & =\mathrm{\frac{[BH]}{[B]+[BH]} } \\
& = \mathrm{\frac{[B]}{[B]}\frac{[BH]/[B]}{1+[BH]/[B]} } \\
& = \mathrm{\frac{[H^+]/K}{1+[H^+]/K} } \\
& = \mathrm{\frac{10^{p\textit{K}-pH}}{1+10^{p\textit{K}-pH}} }
\end{split}
$$ where $$ \mathrm{pH = -log[H^+] \implies [H^+] = 10^{-pH}} $$
and similarly for $K$.
From this we can see that the pK value is the pH value for which $f_{\mathrm{BH}}$ = 1/2. So you compute the pK value from the standard free energy difference
$$\text{p}K =\left( \Delta G^\circ(\mathrm{B})+\Delta G^\circ(\mathrm{H^+})- \Delta G^\circ(\mathrm{BH})\right)/RT\ln(10) $$
and you're done.
Two ionizable groups
For a molecule with two titrateable groups ($ \mathrm{HB_\alpha B_\beta H}$) and the following equilibrium constants $$ \mathrm{HBBH \rightleftharpoons BBH + H^+} \ \ K_{\alpha1}$$ $$\mathrm{HBBH \rightleftharpoons HBB + H^+} \ \ K_{\beta1}$$ $$ \mathrm{HBB \rightleftharpoons BB + H^+} \ \ K_{\alpha0}$$ $$\mathrm{BBH \rightleftharpoons BB + H^+} \ \ K_{\beta0}$$ The probability of, for example, $\mathrm{BBH}$ is $$ f_{\mathrm{BBH}} =\mathrm{\frac{[BBH]}{[BB]+[BBH]+[HBB]+[HBBH]}= \frac{[BBH]}{\textit{P}}} $$ $f_{\mathrm{BBH}}$ can be rewritten in terms of pK values $$f_{\mathrm{BBH}} = \mathrm{\frac{[BBH]/[BB]}{\textit{P}/[BB]} = \frac{10^{p\textit{K}_{\beta0}-pH}}{\textit{P}/[BB]}} $$ where $$ \mathrm{ \textit{P}/[BB] = 1+10^{p\textit{K}_{\alpha0}-pH}+10^{p\textit{K}_{\beta0}-pH}+ 10^{p\textit{K}_{\alpha0}+p\textit{K}_{\beta1}-2pH}} $$ Similarly, $$ f_{\mathrm{HBB}} = \mathrm{\frac{10^{p\textit{K}_{\alpha0}-pH}}{\textit{P}/[BB]}} $$ and $$ f_{\mathrm{HBBH}} = \mathrm{\frac{10^{p\textit{K}_{\alpha0}+p\textit{K}_{\beta1}-2pH}}{\textit{P}/[BB]}} $$ The apparent pK value of the $\alpha$ group ($\mathrm{p}K_{\alpha}$) is the pH at which its protonation probability $$f_\alpha =f_{\mathrm{HBB}} + f_{\mathrm{HBBH}} $$ is 1/2 and similarly for the $\beta$ group. So compute the microscopic pK values (Eq 4-7), then $f_\alpha$ and $f_\beta$ as a function of pH, and then $\mathrm{p}K_{\alpha}$ and $\mathrm{p}K_{\beta}$
If one of the groups (say $\alpha$) titrates at a significantly lower pH than the other ($\mathrm{p}K_{\alpha1} << \mathrm{p}K_{\beta1}$) then $\mathrm{p}K_{\alpha}=\mathrm{p}K_{\alpha1}$ and $\mathrm{p}K_{\beta}=\mathrm{p}K_{\beta0}$ and it is not necessary to compute the free energy of $\mathrm{HBB}$, but it can be hard to determine this in advance. Similarly, if there is no significant interaction between the sites then $\mathrm{p}K_{\alpha}=\mathrm{p}K_{\alpha1}=\mathrm{p}K_{\alpha0}$ and $\mathrm{p}K_{\beta}=\mathrm{p}K_{\beta1}=\mathrm{p}K_{\beta0}$ and one can skip one of the protonation states.
For $N$ ionizable groups one has to determine $2^N$ microscopic pKa values, which quickly gets out of hand if one has to do a conformational search for each protonation state and the molecule is large.
Related post
Generating protonation states and conformations
This work is licensed under a Creative Commons Attribution 4.0
Background: one ionizable group
If there is only one tritrateable site
$$ \mathrm{BH \rightleftharpoons B + H^+} \ \ \ K=\mathrm{\frac{[B][H^+]}{[BH]}} $$
then the fraction of $\mathrm{BH}$ molecules $f_{\mathrm{BH}}$ is $$
\begin{split}
f_{\mathrm{BH}} & =\mathrm{\frac{[BH]}{[B]+[BH]} } \\
& = \mathrm{\frac{[B]}{[B]}\frac{[BH]/[B]}{1+[BH]/[B]} } \\
& = \mathrm{\frac{[H^+]/K}{1+[H^+]/K} } \\
& = \mathrm{\frac{10^{p\textit{K}-pH}}{1+10^{p\textit{K}-pH}} }
\end{split}
$$ where $$ \mathrm{pH = -log[H^+] \implies [H^+] = 10^{-pH}} $$
and similarly for $K$.
From this we can see that the pK value is the pH value for which $f_{\mathrm{BH}}$ = 1/2. So you compute the pK value from the standard free energy difference
$$\text{p}K =\left( \Delta G^\circ(\mathrm{B})+\Delta G^\circ(\mathrm{H^+})- \Delta G^\circ(\mathrm{BH})\right)/RT\ln(10) $$
and you're done.
Two ionizable groups
For a molecule with two titrateable groups ($ \mathrm{HB_\alpha B_\beta H}$) and the following equilibrium constants $$ \mathrm{HBBH \rightleftharpoons BBH + H^+} \ \ K_{\alpha1}$$ $$\mathrm{HBBH \rightleftharpoons HBB + H^+} \ \ K_{\beta1}$$ $$ \mathrm{HBB \rightleftharpoons BB + H^+} \ \ K_{\alpha0}$$ $$\mathrm{BBH \rightleftharpoons BB + H^+} \ \ K_{\beta0}$$ The probability of, for example, $\mathrm{BBH}$ is $$ f_{\mathrm{BBH}} =\mathrm{\frac{[BBH]}{[BB]+[BBH]+[HBB]+[HBBH]}= \frac{[BBH]}{\textit{P}}} $$ $f_{\mathrm{BBH}}$ can be rewritten in terms of pK values $$f_{\mathrm{BBH}} = \mathrm{\frac{[BBH]/[BB]}{\textit{P}/[BB]} = \frac{10^{p\textit{K}_{\beta0}-pH}}{\textit{P}/[BB]}} $$ where $$ \mathrm{ \textit{P}/[BB] = 1+10^{p\textit{K}_{\alpha0}-pH}+10^{p\textit{K}_{\beta0}-pH}+ 10^{p\textit{K}_{\alpha0}+p\textit{K}_{\beta1}-2pH}} $$ Similarly, $$ f_{\mathrm{HBB}} = \mathrm{\frac{10^{p\textit{K}_{\alpha0}-pH}}{\textit{P}/[BB]}} $$ and $$ f_{\mathrm{HBBH}} = \mathrm{\frac{10^{p\textit{K}_{\alpha0}+p\textit{K}_{\beta1}-2pH}}{\textit{P}/[BB]}} $$ The apparent pK value of the $\alpha$ group ($\mathrm{p}K_{\alpha}$) is the pH at which its protonation probability $$f_\alpha =f_{\mathrm{HBB}} + f_{\mathrm{HBBH}} $$ is 1/2 and similarly for the $\beta$ group. So compute the microscopic pK values (Eq 4-7), then $f_\alpha$ and $f_\beta$ as a function of pH, and then $\mathrm{p}K_{\alpha}$ and $\mathrm{p}K_{\beta}$
If one of the groups (say $\alpha$) titrates at a significantly lower pH than the other ($\mathrm{p}K_{\alpha1} << \mathrm{p}K_{\beta1}$) then $\mathrm{p}K_{\alpha}=\mathrm{p}K_{\alpha1}$ and $\mathrm{p}K_{\beta}=\mathrm{p}K_{\beta0}$ and it is not necessary to compute the free energy of $\mathrm{HBB}$, but it can be hard to determine this in advance. Similarly, if there is no significant interaction between the sites then $\mathrm{p}K_{\alpha}=\mathrm{p}K_{\alpha1}=\mathrm{p}K_{\alpha0}$ and $\mathrm{p}K_{\beta}=\mathrm{p}K_{\beta1}=\mathrm{p}K_{\beta0}$ and one can skip one of the protonation states.
For $N$ ionizable groups one has to determine $2^N$ microscopic pKa values, which quickly gets out of hand if one has to do a conformational search for each protonation state and the molecule is large.
Related post
Generating protonation states and conformations
This work is licensed under a Creative Commons Attribution 4.0
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