Parallel Processing of Complex Biomolecular Information: Combining Experimental and Computational Approaches

Abstract

While protein functions such as binding or catalysis remain very difficult to predict computationally from primary sequences, approaches which involve the parallel processing of diverse proteins are remarkably powerful for the isolation of rare proteins with functions of interest. Stated using a Darwinian vocabulary, a repertoire of proteins can be submitted to selection according to a function of interest for isolation of the rare fittest proteins. Parallel processing strategies rely mainly on the design of in vitro selections of proteins. To ensure that complex molecular information can be extracted after selection from protein populations, several types of links between the genotype and the phenotype have been designed for the parallel processing of proteins: they include the display of nascent proteins on the surface of the ribosome bound to mRNA, the display of proteins as fusions with bacteriophage coat proteins and the fusion of proteins to membrane proteins expressed on the surface of yeast cells. In the first two display strategies, covalent and non covalent bonds define chemical links between the genotype and the protein, while in the last case compartmentation by a membrane provides the link between the protein and the corresponding gene. While parallel processing strategies allow the analysis of up to 1014 proteins, serial processing is convenient for the analysis of tens to thousands of proteins, with the exceptions of millions of proteins in the specific case where fluorescent sorting can be adapted experimentally. In this review, the power of parallel processing strategies for the identification of proteins of interest will be underlined. It is useful to combine them with serial processing approaches such as activity screening and the computational alignment of multiple sequences. These molecular information processing (MIP) strategies yield sequence-activity relationships for proteins, whether they are binders or catalysts (Figure 1).