Structures and energetics of the binding of non-natural amino acids to phenylalanyl-tRNA synthetase

Pin Wang, Nagarajan Vaidehi, Nandita Sharma, Kristi Kiick, William Goddard, David Tirrell


We have successfully incorporated analogs of methionine, isoleucine, leucine and phenylalanine into proteins through the action of their respective aminoacyl-tRNA synthetases. Incorporation of new functional groups creates new opportunities for chemical derivatization, extending the range of materials properties that can be designed into protein-based polymers. Incorporation of amino acid analogs into proteins is controlled largely by the corresponding aminoacyl-tRNA synthetases. First-principle computational protocols for docking and scoring have been developed to predict binding energies of phenylalanine analogs to phenylalanyl-tRNA synthetase. The calculated values of binding energies compare favorably with published in vitro activation data and with in vivo incorporation. This indicates that we might be able to use the computational method to identify new substrates for Phe-, Ile- and Met-tRNA synthetases.

Figure 1. Stereo views of the binding site in the PheRS/Phe complex. The docked Phe is shown as pink sticks.

Figure 2. Binding energies (kcal/mol) of ligands in the binding pocket of PheRS shown in figure 1. Substrates to the left of the vertical line can be incorporated in protein in wild-type E. coli cells; those to the right cannot.