Computationally Assisted Noncanonical Amino Acid Incorporation.

Genetic encoding of noncanonical amino acids (ncAAs) with desired functionalities is an invaluable tool for the study of biological processes and the development of therapeutic drugs. However, existing ncAA incorporation strategies are rather time-consuming and have relatively low success rates. Here, we develop a virtual ncAA screener based on the analysis and modeling of the chemical properties of all reported ncAA substrates to virtually determine the recognition potential of candidate ncAAs. Using this virtual screener, we designed and incorporated several novel Lys and Phe derivatives into proteins for various downstream applications. Among them, the genetic encoding of an electron-rich Phe analog, 3-dimethylamino-phenylalanine, was successfully applied to enhance the cation-π interaction between histone methylation and its reader proteins. Thus, our virtual screener provides a fast and powerful strategy to efficiently incorporate ncAAs with diverse functionalities.