Albert Szent-Gyorgyi once defined discovery as seeing what everyone else sees and thinking what no one else thinks. I often find that phenomena that are obvious to other people are not obvious to me. Molecular complementarity is one of these phenomena: while rare among any random set of compounds, it is ubiquitous in living systems. Because every molecule in a living system binds more or less specifically to several others, we now speak of “interactomes”. What explains the ubiquity of molecular complementarity in living systems? What might such an explanation reveal about the chemical origins of life and the principles that have governed its evolution? Beyond this, what might complementarity tell us about the optimization of integrated systems in general?

My research combines theoretical and experimental approaches to molecular complementarity relating to evolution from prebiotic chemical systems to superorganismal interactions. Experimentally, I have characterized complementarity involving specific binding between small molecules and explored how these small-molecule modules have been incorporated into macromolecular systems such as receptors and transporters. Several general principles have emerged from this research. Molecules that bind to each other almost always alter each other’s physiological effects; and conversely, molecules that have antagonistic or synergistic physiological effects almost always bind to each other. This principle suggests a chemical link between biological structure and function. Secondly, modern biological systems contain an embedded molecular paleontology based on complementarity that can reveal their chemical origins. This molecular paleontology is often manifested through modules involving small, molecularly complementary subunits that are built into modern macromolecular structures such as receptors and transporters. A third principle is that complementary modules are conserved and repurposed at every stage of evolution.

Molecular complementarity plays critical roles in the evolution of chemical systems and resolves a significant number of outstanding problems in the emergence of complex systems. All physical and mathematical models of organization within complex systems rely upon nonrandom linkage between components. Molecular complementarity provides a naturally occurring nonrandom linker. More importantly, the formation of hierarchically organized stable modules vastly improves the probability of achieving self-organization, and molecular complementarity provides a mechanism by which hierarchically organized stable modules can form. Finally, modularity based on molecular complementarity produces a means for storing and replicating information. Linear replicating molecules such as DNA or RNA are not required to transmit information from one generation of compounds to the next: compositional replication is as ubiquitous in living systems as genetic replication and is equally important to its functions. Chemical systems composed of complementary modules mediate this compositional replication and gave rise to linear replication schemes.

In sum, I propose that molecular complementarity is ubiquitous in living systems because it provides the physicochemical basis for modular, hierarchical ordering and replication necessary for the evolution of the chemical systems upon which life is based. I conjecture that complementarity more generally is an essential agent that mediates evolution at every level of organization.