Models and Search Strategies for Applied Molecular Evolution

In just a few years, molecular diversity techniques have revolutionized pharmaceutical design and experimental methods for studying receptor binding, consensus sequences, genetic regulatory mechanisms, and many other issues in biochemistry and chemistry. Because of the enormous libraries of ligands that can be used and the rapidity of the techniques, methods of applied molecular evolution such as SELEX and phage display have become particularly popular. These methods have been enormously successful, yet the theoretical work developed for them so far is quite limited. The success of these methods is not trivial: the huge number of sequences being searched through, the low concentrations of individual species, and the noise and biases inherent in the techniques would seem to make these experiments very difficult. Understanding why they work so well, and showing how they can perform better and for more complex molecular search problems, falls under the purview of theory. In this review, I summarize current theoretical approaches to molecular diversity techniques and show the roles they can play in optimizing experimental design and in searching molecular fitness landscapes, a means of relating ligands to their properties.