By the mid-1930s, Pauling was beginning to understand that simply knowing the structures of individual proteins was not enough. The essence of life resulted not from individual molecules, but from the interactions between them. How did organisms make offspring that carried their specific characteristics? How did enzymes recognize and bind precisely to specific substrate molecules? How did the body produce antibodies that recognized and bound to specific foreign, invading antigens? How did proteins, these flexible, delicate, complex molecules, have the uncanny ability to recognize and interact with specific molecules?
These questions all fell under the heading of biological specificity. To this topic Pauling directed much of his attention during the late 1930s and 1940s. To understand biological specificity, Pauling decided to work first with antibodies and antigens, the understanding of which immunologists such as Karl Landsteiner were beginning to perfect. Pauling met and spoke with Landsteiner on several occasions, and he began his own research program in the late 1930s combining Landsteiner's methods with his own most recent chemical techniques. During a decade of antibody experiments, carried out through the late 1940s, Pauling built a detailed picture of the binding of antibody and antigen at the molecular level.
His findings were surprising. Pauling demonstrated that the precise binding of antigen to antibody was accomplished not by typical chemical means, but rather through the shapes of molecules. He discovered that an antibody fits an antigen as a glove fits a hand. Their shapes were complementary. When the fit was tight, the surfaces of antibody and antigen came into very close contact, making possible the formation of many weak bonds that operated at close quarters and were relatively unimportant in traditional chemistry--van der Waals' forces, hydrogen bonds, and so forth. To work, the fit had to be incredibly precise. Even a single atom out of place could significantly affect the binding.
Having demonstrated the importance of complementary structure with antibodies, Pauling extended his idea to other biological systems, including the interaction of enzymes with substrates, odors with olfactory receptors, and even the possibility of genes composed of two complementary molecules.
Pauling's idea that biological specificity was due in great part to complementary "fitting" of large molecules to one another was essential in the development of molecular biology. The path of his research now formed a broad arc, from early work on the chemical bond as a determinant of molecular structure; through finding out the structures of large molecules, first inorganic substances, then biomolecules; and, finally, to elucidating the interactions between large biomolecules. By the early 1950s, Pauling felt that he had discovered the essentials of life at the molecular level. He was ready for something new.