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 EC_w 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 EC_w, 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.