Computational protein design - where it goes?

Proteins have been playing a critical role in the regulation of diverse biological processes related to human life. With the increasing demand, functional proteins are sparse in this immense sequence space. Therefore, protein design has become an important task in various fields, including medicine, food, energy, materials, etc. Directed evolution has recently led to significant achievements. Molecular modification of proteins through directed evolution technology has significantly advanced the fields of enzyme engineering, metabolic engineering, medicine, and beyond. However, it is impossible to identify desirable sequences from a large number of synthetic sequences alone. As a result, computational methods, including data-driven machine learning and physics-based molecular modeling, have been introduced to protein engineering to produce more functional proteins. This review focuses on recent advances in computational protein design, highlighting the applicability of different approaches as well as their limitations.