Abstract
Theoretical analyses are valuable for the exploration of the effects of unnatural amino acids on enzyme functions; however, many necessary parameters for unnatural amino acids remain lacking. In this study, we developed and tested force field parameters compatible with Amber ff14SB for 18 phenylalanine and tyrosine derivatives. The charge parameters were derived from ab initio calculations using the RESP fitting approach and then adjusted to reproduce the benchmark relative energies (at the MP2/TZ level) of the α- and β-backbones for each unnatural amino acid dipeptide. The structures optimized under the proposed force field parameters for the 18 unnatural amino acid dipeptides in both the α- and β-backbone forms were in good agreement with their QM structures, as the average RMSD was as small as 0.1 Å. The force field parameters were then tested in their application to seven proteins containing unnatural amino acids. The RMSDs of the simulated configurations of these unnatural amino acids were approximately 1.0 Å compared with those of the crystal structures. The vital interactions between proteins and unnatural amino acids in five protein–ligand complexes were also predicted using MM/PBSA analysis, and they were largely consistent with experimental observations. This work will provide theoretical aid for drug design involving unnatural amino acids.
Highlights
As is well known, 20 natural amino acids are the main building blocks of proteins, the macromolecules that perform a broad spectrum of functions within organisms (Qin et al, 2015)
For comparison with the B3LYP/6-31G∗ structures, we depict the optimized structures of the 18 Unnatural amino acids (UAAs) dipeptides in the α-state from the initial parameters in Figure 3; the minimized structures for the βstate are shown in Supplementary Figure 1
This work presents the charge parameters of 18 UAAs related to phenylalanine and tyrosine that are compatible with the use of the Amber ff14SB force field included in the GROMACS package
Summary
20 natural amino acids are the main building blocks of proteins, the macromolecules that perform a broad spectrum of functions within organisms (Qin et al, 2015). Unnatural amino acids (UAAs) called noncanonical amino acids are analogs or metabolic intermediates of the 20 natural amino acids with only minor structural differences—often just a chemical functional group—which is beneficial for analyzing their effects on enzyme functions (Zhao et al, 2020). Since UAAs are of high chemical diversity, possess strong site specificity, and introduce little disturbance to the protein structure, it is widely applied in protein engineering, virus vaccine development, and medical therapeutics (Minnihan et al, 2011; Si et al, 2016; Young and Schultz, 2018). UAA-incorporated proteins (such as antibodies, growth factors, and cytokines) interacted with diverse moieties to form bispecific antibodies, antibody-drug conjugates, and pegylated proteins, which provided effective treatments for various clinical testing (Young and Schultz, 2018)
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