Sequence Space and Fitness Landscapes

To study a fitness landscape theoretically, each sequence must also have a defined fitness, so the selective advantage of sequences can 

The structure of a real biopolymer landscape is highly complex. Recently, researchers have started to understand some of the properties of proteins that lead to specific landscape structures. To simplify the problem, it is desirable to identify which physical characteristic of proteins give rise to dynamic trends in evolution. In this section, we review the experimentally deduced properties of coupling and additivity, with the intention of demonstrating that these properties are correlated and discussing the landscape features that they produce. 

During experiments, coupling is observed through non-additive mutational effects. Two mutations are considered additive if the combined change in fitness is equal to the sum of the individual contributions of each mutation. Additivity implies a smooth landscape that can be easily 

Non-additivity arises from the simultaneous disruption of coupled residues by multiple mutations. Mutations affecting some functions, such as protein-protein and DNA-protein interactions, tend to be remarkably additive, while others, such as mutations in the catalytic site, tend to be non-additive (Jencks, 1981 Wells, 1990). Mutational studies on T4 lysozyme (Zhang et al., 1995) and catalase I (Trakulnaleamsai et al., 1995) indicate that thermostability is largely additive, and therefore relatively uncoupled. Non-additivity is most commonly observed when the mutated residues are close in space and large, or when chemically disparate side chains are introduced. 

LiCata and Ackers report that mutations that are not directly in contact can be non-additive (1995). They find that most mutations exhibit some degree of non-additivity that cannot be explained by short-range disruptions. A structural study of mutants of pNB esterase generated by directed evolution supports this observation (Spiller et al., 1999 see chapter by Orencia, Hanson, and Stevens in this volume). In this case, the influence of a mutation was realized through small backbone shifts, spatially distant from the mutated residue. Non-additivity can result when these perturbed regions overlap (Skinner and Terwilliger, 1996). 

---