A molecular dynamics simulation study of amino acid selectivity of LeuRS editing domain from Thermus thermophilus

Rayevsky, Alexey; Sharifi, Mohsen; Tukalo, M. A.

doi:10.1016/j.jmgm.2018.06.015

Cited by 6 publications

(6 citation statements)

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“…Based on the dual norvalyl-and isoleucyl-tRNA model, we managed to predict a common binding mode in LeuRS from bacteria and archaea, however, with different directions of the water attack, as it was reported previously. 20,21 ■ CONCLUSIONS One of the most important findings of these in silico experiments on aminoacyl-tRNAs using the RESP charge deviation method is the development of accurate and adjustable topologies, which are not possible to create with different third-party software. The specificity of the Amber force field is rendered challenging to reproduce a correct charge distribution for such molecules like aminoacyls, which comprise both amino acid and nucleic moieties.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…We used an optimized geometry of the entire complex to extract the coordinates of norvalyl-tRNA (PDB-ID: 2BTE) and docking poses for isoleucyl- and leucyl-tRNA (Figure ). , The same approach was used for the study of alanyl-tRNA binding in the prolyl-tRNA synthetase (PDB-ID: 2J3M). , All details for ligand–protein and nucleic acid–protein docking protocols with Gold CCDC , are already described in previous studies .…”

Section: Computational Methodsmentioning

confidence: 99%

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Effect of Charge Distribution in a Modified tRNA Substrate on Pre-Reaction Protein-tRNA Complex Geometry

et al. 2021

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Computational Methodsmentioning

confidence: 99%

Effect of Charge Distribution in a Modified tRNA Substrate on Pre-Reaction Protein-tRNA Complex Geometry

et al. 2021

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“…The highly similar interaction patterns for IleRS, ValRS, and MetRS substantiate this assumption. Due to their difficult discrimination, editing functionality is key 5 , 56 , 92 , 102 , 103 for these aaRSs.…”

Section: Discussionmentioning

confidence: 99%

The structural basis of the genetic code: amino acid recognition by aminoacyl-tRNA synthetases

Kaiser

Krautwurst

Salentin

et al. 2020

Sci Rep

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Storage and directed transfer of information is the key requirement for the development of life. Yet any information stored on our genes is useless without its correct interpretation. The genetic code defines the rule set to decode this information. Aminoacyl-tRNA synthetases are at the heart of this process. We extensively characterize how these enzymes distinguish all natural amino acids based on the computational analysis of crystallographic structure data. The results of this meta-analysis show that the correct read-out of genetic information is a delicate interplay between the composition of the binding site, non-covalent interactions, error correction mechanisms, and steric effects. One of the most profound open questions in biology is how the genetic code was established. While proteins are encoded by nucleic acid blueprints, decoding this information in turn requires proteins. The emergence of this self-referencing system poses a chicken-or-egg dilemma and its origin is still heavily debated 1,2. Aminoacyl-tRNA synthetases (aaRSs) implement the correct assignment of amino acids to their codons and are thus inherently connected to the emergence of genetic coding. These enzymes link tRNA molecules with their amino acid cargo and are consequently vital for protein biosynthesis. Beside the correct recognition of tRNA features 3 , highly specific non-covalent interactions in the binding sites of aaRSs are required to correctly detect the designated amino acid 4-7 and to prevent errors in biosynthesis 5,8. The minimization of such errors represents the utmost barrier for the development of biological complexity 9 and accurate specification of aaRS binding sites is proposed to be one of the major determinants for the closure of the genetic code 10. Beside binding side features, recognition fidelity is controlled by the ratio of concentrations of aaRSs and cognate tRNA molecules 11 and may involve spatial secondary structures motifs in addition to side chain configurations 12,13. Evolution. The evolutionary origin of aaRSs is hard to track. Phylogenetic analyses of aaRS sequences show that they do not follow the standard model of life 14 ; the development of aaRSs was nearly complete before the Last Universal Common Ancestor (LUCA) 15,16. Their complex evolutionary history included horizontal gene transfer, fusion, duplication, and recombination events 14,17-21. Sequence analyses 22 and subsequent structure investigations 23,24 revealed that aaRSs can be divided into two distinct classes (Class I and Class II) that share no similarities at sequence or structure level. Each of the classes is responsible for 10 of the 20 proteinogenic amino acids and can be further grouped into subclasses 15. One exception to this class separation rule is lysyl-tRNA synthetase (LysRS), where euryarchaeal genomes were shown to contain a Class I form 25 instead of the standard Class II form. Most eukaryotic genomes contain the complete set of 20 aaRSs. However, some species lack certain aaRS-encoding genes and compensate for this by ...

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“…The greatest advantage is the fact, that topologies with RESP parameters are ready for straight implementation in a force field without any other refinements. However, the best result can be obtained after comparison of computational and experimental approaches, like it was done with prolyl-tRNA and leucyl-tRNA systems [10,17,18], to correct some inconsistency and set up the system.…”

Section: Discussionmentioning

confidence: 99%

Computational approaches for parameterization of aminoacyl-tRNA synthetase substrates

Rayevsky

Tukalo

2018

Biopolym. Cell

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Aim.To parameterize a modified chained residue and use a newborn topology for molecular dynamics simulation. Method. To deal with the problem, a series of ab initio and semi-empirical methods were combined. The RESP (Restrained ElectroStatic Potential) program, which fits molecular electrostatic potential (MEP) at molecular surfaces using an atom-centered point charge model. All parameters were quantum mechanically calculated and processed with R.E.D.III server. Results. The method of molecular dynamics has potential advantages, like its capability to explore large systems, and disadvantages, like not being feasible to run on fly without a preliminary prepared topologies for identification of each molecule. In an attempt to find a balance between both features speed and accuracy and apply the approach in a computational study, a functional mechanism of prolyl-tRNA synthetase from E.faecalis was investigated. In addition, a well validated protocol of topology preparation for non-canonical structure was developed. Conclusions. Computational approaches like molecular dynamics simulation and molecular docking had now become a strong in silico methods to study biological processes. The major benefits of this methods are expensiveness and speed. It also a strong competitor of quantum modeling approach. However, there is a need to include new structures that are not exist in the GROMACS library is associated with the growing use of different types of modified amino and nucleic acids (DNA derivatives and RNAs) both in fundamental studies in molecular biology, molecular biophy sics, etc., and in applied research related to the search for new drugs. The obtained data well correlate with the experimental data. K e y w o r d s: force field, RESP, R.E.D.III, molecular dynamics, aminoacyl-tRNA synthetase

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A molecular dynamics simulation study of amino acid selectivity of LeuRS editing domain from Thermus thermophilus

Cited by 6 publications

References 41 publications

Effect of Charge Distribution in a Modified tRNA Substrate on Pre-Reaction Protein-tRNA Complex Geometry

Effect of Charge Distribution in a Modified tRNA Substrate on Pre-Reaction Protein-tRNA Complex Geometry

The structural basis of the genetic code: amino acid recognition by aminoacyl-tRNA synthetases

Computational approaches for parameterization of aminoacyl-tRNA synthetase substrates

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