Teaching molecular interactions and coupling in binding reactions

Students beginning their study of biochemistry or biophysics at the undergraduate level are often overwhelmed by the complexity of the systems and the nomenclature. By comparison, chemical systems appear simple to them, as students can more easily relate to introductory chemistry courses, where the molecules are smaller and bind yet smaller ions. This allows students to write the structure of the entire molecule on a piece of paper and see exactly to which functional groups an ion, such as a proton (H+) in the simplest case, binds. Yet concepts that are fundamental in biochemical macromolecules, namely proteins, can perfectly well be taught at the undergraduate level, and probably be more easily understood, by using simpler, strictly chemical examples, which are already familiar to the students. For example, the concepts of interacting binding sites, which are at the root of cooperativity in protein binding reactions and conformational changes, are already present in simple molecules such as EDTA. In this paper, we show how to accomplish this goal by treating the binding of protons to EDTA in a very conceptual way, using the idea of the partition function and intramolecular interactions, rather than a formal algebraic approach. By doing so, the concepts of interacting sites appear naturally, in a small molecule where their origin can be easily ascribed—in this case, mainly to electrostatic interactions. Equipped with this understanding and this approach, students will be able to tackle more complicated biophysical systems, where the molecules are larger but the concepts are the same.