In Silico Protein Design

Proteins mediate many essential processes of life to a degree of functional precision unmatched by any synthetic device. The emerging field of in silico protein design is predicted to provide the next quantum leap in the biotech industry. Having predictive control over protein function and the ability to redefine these functions have driven the field of protein engineering into an era of unprecedented development. MedAI provides a holistic introduction of protein design R&D (current state-of-the-art tools and know-how), as well as a one-stop-shop profile of in silico protein design technology.

Schematics of in silico protein designFigure 1 Schematics of in silico protein design

Efforts have begun to combine the goals and approaches of computational molecular design and protein sequence analysis to provide tools for the rational mutagenesis and functional modification of proteins. These approaches use analysis of the three-dimensional structure of a protein to guide the selection of appropriate amino acid sequences to create desired properties or functions. The convergence of low-cost, high-speed computers, a tremendous increase in protein structure information, and a growing understanding of the forces that control protein structure has resulted in dramatic advances in the ability to control protein function and structure and to create the truly artificial proteins. Various academic software packages have been developed for in silico protein design.

Protein engineering strategies aimed at constructing enzymes with novel or improved activities, specificity, and stabilities greatly benefit from in silico methods such as bioinformatics, molecular modelling, and de novo design. Computational approaches offer significant potential for engineering protein structure and function and can be combined with experimental testing to gain new insights into the fundamental properties of proteins. It is based on altering the affinity of a protein by replacing some amino-acid residues to identify the essential residues and their specific involvement in the binding activity.

Protein Engineering Strategies
Site-directed mutagenesis Target sites may be selected by sequence comparison or structural analysis.
Directed evolution Mutant libraries are created with random or semirandom mutagenesis such as error-prone polymerase chain reaction, DNA shuffling, or RECODE and selected by cell growth and/or survival or screened via high-/medium-throughput screening.
In silico protein design The design goals could be redesigning the functionality or stability of a known protein or designing a protein de novo. The design space is defined according to the goals (e.g., redesign protein to increase stability or alter substrate specificity). Desired conformations and sequences are computed according to the defined constraints.

Compared to directed evolution or site-directed mutagenesis, in silico protein design allows more rapid protein evolution. As protein structure dictates its function, in silico protein design seeks to construct new structures that fit the desired protein function and compute sequences that have the designed structure as their free energy minimum folding. It may start using an existing protein structure as the backbone (protein redesign) or from scratch (de novo protein design). The application of in silico protein design has produced various protein materials, biosensors, protein therapeutics, and biocatalysts.

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