Xiaowen Wang1,2, Wenjin Li1. 1. Institute for Advanced Study, Shenzhen University, Shenzhen, China. 2. College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, China.
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.
Theoretical analyses are valuable an class="Chemical">for the exploration oan class="Chemical">f the effects ofunnatural 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 wasas 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.
Authors: Tianyi Yang; Johnny C Wu; Chunli Yan; Yuanfeng Wang; Ray Luo; Michael B Gonzales; Kevin N Dalby; Pengyu Ren Journal: Proteins Date: 2011-04-12
Authors: Kai P Yuet; Meenakshi K Doma; John T Ngo; Michael J Sweredoski; Robert L J Graham; Annie Moradian; Sonja Hess; Erin M Schuman; Paul W Sternberg; David A Tirrell Journal: Proc Natl Acad Sci U S A Date: 2015-02-17 Impact factor: 11.205