Mathematics-assisted directed evolution and protein engineering

Abstract

Directed evolution is a molecular biology technique that is transforming protein engineering by creating proteins with desirable properties and functions. However, it is experimentally impossible to perform the deep mutational scanning of the entire protein library due to the enormous mutational space, which scales as $20^N$ , where N is the number of amino acids. This has led to the rapid growth of AI-assisted directed evolution (AIDE) or AI-assisted protein engineering (AIPE) as an emerging research field. Aided with advanced natural language processing (NLP) techniques, including long short-term memory, autoencoder, and transformer, sequence-based embeddings have been dominant approaches in AIDE and AIPE. Persistent Laplacians, an emerging technique in topological data analysis (TDA), have made structure-based embeddings a superb option in AIDE and AIPE. We argue that a class of persistent topological Laplacians (PTLs), including persistent Laplacians, persistent path Laplacians, persistent sheaf Laplacians, persistent hypergraph Laplacians, persistent hyperdigraph Laplacians, and evolutionary de Rham-Hodge theory, can effectively overcome the limitations of the current TDA and offer a new generation of more powerful TDA approaches. In the general framework of topological deep learning, mathematics-assisted directed evolution (MADE) has a great potential for future protein engineering.