Rayevsky Alexey, Sharifi Mohsen, Demianenko Eugeniy, Volochnyuk Dmitriy, Tukalo Michael
Department of Protein Synthesis Enzymology, Institute of Molecular Biology and Genetics National Academy of Sciences of Ukraine, Osipovskogo st. 2a, Kyiv, UA 03143, Ukraine.
Laboratory of Bioinformatics and Structural Biology, Institute of Food Biotechnology and Genomics National Academy of Sciences, Osipovskogo 2a Str., Kyiv, 04123, Ukraine.
ACS Omega. 2021 Feb 3;6(6):4227-4235. doi: 10.1021/acsomega.0c05143. eCollection 2021 Feb 16.
An important aspect of molecular mechanics simulations of a protein structure and ligand binding often involves the generation of reliable force fields for nonstandard residues and ligands. We consider the aminoacyl-tRNA synthetase (AaRS) system that involves nucleic acid and amino acid derivatives, obtaining force field atomic charges using the restrained electrostatic potential (RESP) approach. These charges are shown to predict observed properties of the post-transfer editing reaction in this system, in contrast to simulations performed using approximate charges conceived based upon standard charges for related systems present in force field databases. In particular, the simulations predicted key properties induced by mutation. The approach taken for generating the RESP charges retains established charges for known fragments, defining new charges only for the novel chemical features present in the modified residues. This approach is of general relevance for the design of force fields for pharmacological applications, and indeed the AaRS target system is itself relevant to antibiotics development.
蛋白质结构与配体结合的分子力学模拟的一个重要方面通常涉及为非标准残基和配体生成可靠的力场。我们考虑涉及核酸和氨基酸衍生物的氨酰 - tRNA合成酶（AaRS）系统，使用受限静电势（RESP）方法获得力场原子电荷。与使用基于力场数据库中相关系统的标准电荷构想的近似电荷进行的模拟相比，这些电荷被证明能够预测该系统中转录后编辑反应的观察到的性质。特别是，模拟预测了由突变诱导的关键性质。生成RESP电荷所采用的方法保留了已知片段的既定电荷，仅为修饰残基中存在的新化学特征定义新电荷。这种方法对于药物应用的力场设计具有普遍相关性，实际上AaRS目标系统本身与抗生素开发相关。
