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.