Predicting Uncoupling Toxicity of Organic Acids Based on Their Molecular Structure Using a Biophysical Model

We present a purely
mechanistic model to predict protonophoric
uncoupling activity ECw of organic acids. All required
input information can be derived from their chemical structure. This
makes it a convenient predictive model to gain valuable information
on the toxicity of organic chemicals already at an early stage of
development of new commercial chemicals (e.g., in agriculture or pharmaceutical
industries). A critical component of the model is the consideration
of the possible formation of heterodimers from the neutral and anionic
monomer, and its permeation through the membrane. The model was tested
against literature data measured in chromatophores, submitochondrial
particles, isolated mitochondria, and intact green algae cells with
good success. It was also possible to reproduce pH-dependencies in
isolated mitochondria and intact cells. Besides the prediction of
the ECw, the mechanistic nature of the model allows researchers
to draw direct conclusions on the impact of single input factors such
as pH- and voltage-gradients across the membrane, the anionic and
neutral membrane permeability, and the heterodimerization constant.
These insights are of importance in drug design or chemical regulation.