Applied molecular evolution

The desire to create RNA molecules with predefined properties and to optimize their efficiencies and specificities has led to a new technique called evolutionary biotechnology or applied molecular evolution. Natural selection or its analogue in test-tube evolution optimizes fitness or replication rate constants, respectively. High replication rates, however, are neither required nor wanted in the search for... 

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 [1-6]. 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 [1,5,7-11],... 

At present, many popular applied molecular evolution protocols do not involve mutation or recombination. The laboratory technique-based models presented in this section are of this type. Incorporating mutation requires fitness landscape models or some other means of relating molecular properties to particular sequences. The more abstract models reviewed later allow for mutation and recombination and are based heavily on landscape structure. The models in the present section are based on affinity distribution p(Ka), the probability that a ligand chosen at random from the library has affinity Ka. 

To my knowledge, there are only three laboratory technique-based models for applied molecular evolution. Each is reviewed in detail here. 

In applied molecular evolution, fitness generally has one of two meanings (i) It can refer specifically to how well a molecule performs a desired function, typically the affinity of a ligand for a given receptor or its catalytic activity for a given reaction, (ii) It can refer to the rate at which a molecule in a population of molecules is copied over one iteration, similar to the notion of enrichment in die molecular diversity literature. This second definition is more complex, as fitness depends not only on the properties of a molecule but also on the properties of the rest of the population. Since fitness then changes each iteration as the population changes, the whole fitness landscape metaphor is weakened. For these reasons, I will restrict myself to the first definition of fitness. 

Any theoretical study of applied molecular evolution needs information on the fitnesses of the molecules in the search space, as it is not possible to characterize the performance of search algorithms without knowing properties of the landscape being searched [63], Since the ideals of sequence-to-structure or sequence-to-function models are not yet possible, it is necessary to use approximations to these relationships or make assumptions about their functional form. To this end, a large variety of models have been developed, ranging from randomly choosing affinities from a probability distribution to detailed biophysical descriptions of sequence-structure prediction. These models are often used to study protein folding, the immune system and molecular evolution (the study of macromolecule evolution and the reconstruction of evolutionary histories), but they can also be used to study applied molecular evolution [4,39,53,64-67], A number ofthese models are reviewed below. 

The theory to calculate these relationships, particularly in the context of applied molecular evolution, is still sparse. The remainder of this section highlights some potentially very useful concepts and approaches for experiment protocol design. The summary of literature here is by no means complete. 

The mathematical analyses of evolutionary dynamics on spin glass-like landscapes and the statistical mechanics and exact solution approaches to genetic algorithms can be related to the techniques and parameters used in laboratories. If performance measures of importance in applied molecular evolution are related to the approximated affinity... 

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