Protein design

Protein design is the rational design of new protein molecules to fold to a target protein structure, with the end goal of designing novel function and/or behavior. Proteins can be designed from scratch (de novo design) or by making calculated variants of a known protein structure and its sequence (termed protein redesign). Rational protein design approaches make protein-sequence predictions that will fold to specific structures. These predicted sequences can then be validated experimentally through methods such as peptide synthesis, site-directed mutagenesis, or artificial gene synthesis.

Rational protein design dates back to the mid-1970s, although initial protein design approaches were based mostly on sequence composition and did not account for specific interactions between side-chains at the atomic level. Recently, however, improvements in molecular force fields, protein design algorithms, and structural bioinformatics, such as libraries of amino acid conformations, have enabled the development of advanced computational protein design tools. These computational tools can make complex calculations on protein energetics and flexibility, and perform searches over vast configuration spaces, which would be unfeasible to perform manually. Due to the development of computational protein design programs, and important successes in the field (e.g., see examples below), rational protein design has become one of the most important tools in protein engineering.

The goal in rational protein design is to predict amino acid sequences that will fold to a specific protein structure. Although the number of possible protein sequences is vast, growing exponentially with the size of the protein chain, only a subset of them will fold reliably and quickly to one native state. Protein design involves identifying novel sequences within this subset. The native state of a protein is the conformational free energy minimum for the chain. Thus, protein design is the search for sequences that have the chosen structure as a free energy minimum. In a sense, it is the reverse of protein structure prediction. In design, a tertiary structure is specified, and a sequence that will fold to it is identified. Hence, it is also termed inverse folding. Protein design is then an optimization problem: using some scoring criteria, an optimized sequence that will fold to the desired structure is chosen.

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