calc_ionization: Calculate the ionization.

In httk: High-Throughput Toxicokinetics

Calculate the ionization.

Description

This function calculates the ionization of a compound at a given pH. The pKa's are either entered as parameters or taken from a specific compound in the package. The arguments pKa_Donor and pKa_Accept may be single numbers, characters, or vectors. We support characters because there are many instances with multiple predicted values and all those values can be included by concatenating with commas (for example, pKa_Donor = "8.1,8.6". Finally, pka_Donor and pKa_Accept may be vectors of characters representing different chemicals or instances of chemical parameters to allow for uncertainty analysis. A null value for pKa_Donor or pKa_Accept is interpretted as no argument provided, while " " is taken as a prediction of no ionization possible at any pH.

Usage

calc_ionization(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  parameters = NULL,
  pH = NULL,
  pKa_Donor = NULL,
  pKa_Accept = NULL,
  return_charge_matrix = FALSE
)

Arguments

chem.cas	Either the chemical name or the CAS number must be specified.
chem.name	Either the chemical name or the CAS number must be specified.
dtxsid	EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs
parameters	Chemical parameters from a parameterize_MODEL function, overrides chem.name and chem.cas.
pH	pH where ionization is evaluated.
pKa_Donor	Compound H dissociation equilibirum constant(s). Overwrites chem.name and chem.cas.
pKa_Accept	Compound H association equilibirum constant(s). Overwrites chem.name and chem.cas.
return_charge_matrix	If TRUE, the function returns a table describing each ionization state considered by the calculations in this function (defaults to FALSE)

Details

It is very important to note that pKb = 14 - pKa. But if a predictor gives us a doinor pKa, we just accept it as a pKa.

For hydrogen donor sites, a hydrogen is present in the molecule that can be donated to the solution if the concentration of hydrogens gets low enough. This causes the molecule to become more negatively charged. This is an acid. For hydrogen acceptor suits a location exist in the molecule that can accept an additional history if the concentration of hydrogens gets sufficiently high. This causes the molecule to become more positively charged. This is a base.

We make several assumptions about ionization in order to make our calculations. First, we assume ionization is either due to either "donating" (losing) a hydrogen ion (a positively charge proton) to the solution or by "accepting" (gaining) a hydrogen ion from the solution. Generally, acids are hydrogen donors and bases are hydrogen acceptors. Second, pH is the negative log10 concentration of hydrogen atoms. The lower the pH, the more hydrogen atoms. So, acids donate their hydrogen atoms as pH of the solution increases. Bases accept their hydrogen atoms as pH decreases. Third, each predicted pKa is a prediction that a specific location (or site) on molecule X can either donate or accept a hydrogen. Fourth, the pKa value indicates the pH at which half of the molecules of X have ionized at the site, and half have not. The concentration of the two forms are equal. Fifth, if there are N pKa's for molecule X, then there are N sites that can ionize. Technically this means that there are 2^N different ionization states for molecule X (where each site is or is not ionized). However, pKa predictors give the equlibrium only for pairs of ionization states. So, we only consider N + 1 ionizations states for X – the state immediately above and below each pKa.

To understand the different charge states we annotate the nonionizable backbone of a molecule as "X". For each site on X that is capable of donating a hydrogen we add a "D" to the right of "X". For each site on X that has accepted a hydrogen, we add a "A" to the right of "X". We read the A's and D's from left to right, with the one occuring at the lowest pH first. So a typical acid ionization would be: XD -> X- and a typical base ionization would be XA+ -> X. Where things get complicated is if there are multiple donor and acceptor states. In particular, it is possible for a compound to have a net zero charge, but be simultaneously positively and negatively charged. Such a state is called a Zwitter ion. For example: XDAA+ -> XAA++ -> XA+ -> XA -> X- . The state XA is technically neutral because X has donated one hydrogen, but also accepted one hydrogen. XA is a Zwitter ion.

Each pKa gives the equlibrium ratio of two states pH - pKa = log10[X/XD] for donation or pOH - pka = log10[X/XA] for accepting. pOH = 14 - pH. Separating the logarithm into log10[X] - log10[XD] lets us see that Cn = Xn - Xn-1 where Cn = pH -pKa for donor pKa's and Cn = 14 - pH - pKa for acceptor pKa's. We can rewrite log10Xn = Sum_i=1:n Ci + log10X1. So we can calculate each Xn by summing all the ratios between Xn and the lowest state (X1). Then, by requiring that all Xi sum to 1, we have: 1 = Sum_i=1:N 10^Xi = Sum_i=1:N 10^(Sum_j=1:i (Cj + log10X1)) = X1 * Sum_i=1:N 10^(Sum_j=1:i Cj) so that X1 = 1 / Sum_i=1:N 10^(Sum_j=1:i Cj)

The sum im the denominator is the ratio from X1 to each state (including X1). We use a table called "charge_matrix" to keep track of all N + 1 ionization states and the ratio of each state to the next. We use these ratios to calculate

Value

fraction_neutral	fraction of compound neutral
fraction_charged	fraction of compound charged
fraction_negative	fraction of compound negative
fraction_positive	fraction of compound positive
fraction_zwitter	fraction of compound zwitterionic
charge_matrix	Description of each ionization state if argument return_charge_matrix==TRUE

Author(s)

Robert Pearce and John Wambaugh

References

\insertRef

pearce2017evaluationhttk

\insertRef

strope2018highhttk

Examples

# Neutral compound:
calc_ionization(chem.name="Acetochlor",pH=7.4)

# Donor pKa's 9.78,10.39 -- Should be almost all neutral at plasma pH:
out <- calc_ionization(chem.name='bisphenola',pH=7.4)
print(out)
out[["fraction_neutral"]]==max(unlist(out))

# Donor pKa's 9.78,10.39 -- Should be almost all negative (anion) at higher pH:
out <- calc_ionization(chem.name='bisphenola',pH=11)
print(out)
out[["fraction_negative"]]==max(unlist(out))

# Ficticious compound, should be almost all all negative (anion):
out <- calc_ionization(pKa_Donor=8,pKa_Accept="1,4",pH=9)
print(out)
out[["fraction_negative"]]>0.9

# Donor pKa 6.54 -- Should be mostly negative (anion):
out <- calc_ionization(chem.name='Acephate',pH=7)
print(out)
out[["fraction_negative"]]==max(unlist(out))

#Acceptor pKa's "9.04,6.04"  -- Should be almost all positive (cation) at plasma pH:
out <- calc_ionization(chem.cas="145742-28-5",pH=7.4)
print(out)
out[["fraction_positive"]]==max(unlist(out))

#Ficticious Zwitteron:
out <- calc_ionization(pKa_Donor=6,pKa_Accept="8",pH=7.4)
print(out)
out[["fraction_zwitter"]]==max(unlist(out))

httk documentation built on June 8, 2025, 12:19 p.m.