A study of communication pathways in methionyl- tRNA synthetase by molecular dynamics simulations and structure network analysis - PubMed (original) (raw)

A study of communication pathways in methionyl- tRNA synthetase by molecular dynamics simulations and structure network analysis

Amit Ghosh et al. Proc Natl Acad Sci U S A. 2007.

Abstract

The enzymes of the family of tRNA synthetases perform their functions with high precision by synchronously recognizing the anticodon region and the aminoacylation region, which are separated by approximately 70 A in space. This precision in function is brought about by establishing good communication paths between the two regions. We have modeled the structure of the complex consisting of Escherichia coli methionyl-tRNA synthetase (MetRS), tRNA, and the activated methionine. Molecular dynamics simulations have been performed on the modeled structure to obtain the equilibrated structure of the complex and the cross-correlations between the residues in MetRS have been evaluated. Furthermore, the network analysis on these simulated structures has been carried out to elucidate the paths of communication between the activation site and the anticodon recognition site. This study has provided the detailed paths of communication, which are consistent with experimental results. Similar studies also have been carried out on the complexes (MetRS + activated methonine) and (MetRS + tRNA) along with ligand-free native enzyme. A comparison of the paths derived from the four simulations clearly has shown that the communication path is strongly correlated and unique to the enzyme complex, which is bound to both the tRNA and the activated methionine. The details of the method of our investigation and the biological implications of the results are presented in this article. The method developed here also could be used to investigate any protein system where the function takes place through long-distance communication.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

The overall docked structure of E. coli MetRS–tRNAfMet complex along with Met AMP.

Fig. 2.

Fig. 2.

MD trajectories of RMSD of the four systems (A, B, C, and D) of MeRS with reference to the minimized crystal structure. A, B, C and D in this figure and in subsequent figures correspond to the simulations on four systems: MetRS (A), MetRS-MetAMP (B), MetRS–tRNAfMet (C), and MetRS–tRNAfMet–MetAMP (D).

Fig. 3.

Fig. 3.

Recognition of the anticodon C34–A35–U36 of tRNAfMet by MetRS for systems C (a) and D (b) at 8.0 ns of simulation. The interacting protein region is shown as a transparent gray ribbon. The bases in the anticodon region and the interacting amino acids are shown as lines. The dynamically stable hydrogen bonds are shown by dotted lines.

Fig. 4.

Fig. 4.

DCCM representing the collective atom fluctuation for system D. The strong (Cij = ±0.7–1.0), moderate (Cij = ±0.5–0.7), and weak (Cij = ±0.3–0.5) ones are represented by black, dark gray, and light gray, respectively. The lower and upper triangles correspond to negative and positive correlations, respectively. The numbers 4–550 correspond to MetRS residues. The residue numbers corresponding to different domains are marked: 4–99, 251–322, Rossmann fold domain; 100–250, CP domain; 323–388, KMSKS domain; 389–550, anticodon binding domain; 550–76, tRNA. The correlated residues enclosed in rectangular boxes are involved in the shortest pathways of communication, the details of which are given in Table 2.

Fig. 5.

Fig. 5.

Four communication pathways between the active site and the anticodon binding region as detected by the PSN analysis of noncovalent interaction in system D. The residues in bold are in the interface of the anticodon binding domain and the catalytic plus KMSKS domains.

Fig. 6.

Fig. 6.

Pictorial representation of the shortest paths (between Leu-13 and the anticodon binding residues Trp-461, Asn-391, and Arg-395) shown in Fig. 5 [(a) paths I and III; (b) paths II and IV)]. In both a and b, the residues participating in the communication paths and MetAMP are shown as spheres, MetAMP is shown in magenta, and Leu-13 and Trp-461 are shown in orange. The residues common between the paths I and III in a and between II and IV in b also are shown in orange. The residues that are exclusive to paths I and III are shown in violet and blue, respectively, in a, and the residues that are exclusive to paths II and IV are shown in yellow and cyan, respectively, in b. Light green, anticodon binding domain; gray, active site and KMSKS domains; purple blue, linker peptide; lemon green, CP domain; brown, tRNA.

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