Parameterization of Unnatural Amino Acids with Azido and Alkynyl R‑Groups for Use in Molecular Simulations

Recent new methods to functionalize proteins at specific amino acid locations use unnatural amino acids that contain azido and alkynyl groups. This capability is unprecedented and enables the creation of site-specific protein devices. Because of the high specificity of these devices, many protein configurations are possible and in silico screens have shown promise in predicting optimal attachment site locations. Therefore, there is significant interest in improving current molecular dynamics (MD) models to include the unique chemistries of these linear moieties. This work uses the force field tool kit to obtain the bonded and nonbonded CHARMM parameters for small molecules that contain azido and alkynyl groups. Next, the reliability of these parameters is tested by running simulated MD analysis to prove that the modeled structures match those found in the literature and quantum theory. Finally, the protein MD simulation compares this parameter set with crystallographic data to give a greater understanding of unnatural amino acid influence on the protein structure.