Ligand dependent intra and inter subunit communication in human tryptophanyl tRNA synthetase as deduced from the dynamics of structure networks

Abstract

Homodimeric protein tryptophanyl tRNA synthetase (TrpRS) has a Rossmann fold domain and belongs to the 1c subclass of aminoacyl tRNA synthetases. This enzyme performs the function of acylating the cognate tRNA. This process involves a number of molecules (2 protein subunits, 2 tRNAs and 2 activated Trps) and thus it is difficult to follow the complex steps in this process. Structures of human TrpRS complexed with certain ligands are available. Based on structural and biochemical data, mechanism of activation of Trp has been speculated. However, no structure has yet been solved in the presence of both the tRNA(Trp) and the activated Trp (TrpAMP). In this study, we have modeled the structure of human TrpRS bound to the activated ligand and the cognate tRNA. In addition, we have performed molecular dynamics (MD) simulations on these models as well as other complexes to capture the dynamical process of ligand induced conformational changes. We have analyzed both the local and global changes in the protein conformation from the protein structure network (PSN) of MD snapshots, by a method which was recently developed in our laboratory in the context of the functionally monomeric protein, methionyl tRNA synthetase. From these investigations, we obtain important information such as the ligand induced correlation between different residues of this protein, asymmetric binding of the ligands to the two subunits of the protein as seen in the crystal structure analysis, and the path of communication between the anticodon region and the aminoacylation site. Here we are able to elucidate the role of dimer interface at a level of detail, which has not been captured so far.

Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis

“…Graph theory based cluster analysis of the structures has been shown to elucidate the different types of interfaces in multimeric proteins such as lectins [17] and tryptophanyl-tRNA synthetase [38]. In the present study of the dimeric protein LuxS, the interface clusters present in the snapshots from the simulations are identified (using the algorithm Depth First Search ).…”

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

“…[84] A combination of molecular dynamics (MD) simulations and protein structure network analysis can identify functionally important sites and structural changes in the conformational populations of states. [85][86][87][88][89][90][91][92] Graph-based protein networks that incorporated the interaction residue connectivity and combined this model with dynamic contact maps of cross-correlations described allosteric communications in tRNAÀprotein complexes, [93] cysteinyl tRNA synthetase, [94,95] imidazole glycerol phosphate synthase, [96,97] thrombin, [98] and the M2 muscarinic receptor. [99] 3 The Hsp90 Chaperone: Structural Studies…”

Allosteric Regulation of the Hsp90 Dynamics and Stability by Client Recruiter Cochaperones: Protein Structure Network Modeling

“…A combination of MD simulations and the protein structure network analysis using a graph-based representation of the residue interactions can identify functionally important sites and subtle structural changes in the conformational populations of states [80]–[87]. Graph-based protein networks that incorporated dynamic contact maps of cross-correlations with the interaction residue connectivity have successfully described allosteric communications in tRNA–protein complexes [88], cysteinyl tRNA synthetase [89], [90], imidazole glycerol phosphate synthase [91], [92], thrombin [93], and the M2 muscarinic receptor [94].…”