A Comparative Study of All-atom Molecular Dynamics Simulation and Coarse-grained Normal Mode Analysis in Identifying Pre-existing Residue Interaction Networks that Promote Coupled-Domain Dynamics in Escherichia coli Methionyl-tRNA Synthetase

Inter-domain communication plays a key role in the function of modular proteins. Earlier studies have demonstrated that the coupling of domain motions is important in mediating site-to-site communications in modular proteins. In the present study, bioinformatics and molecular simulations were used to trace “pre-existing” residue-residue interaction networks that mediate coupled-domain dynamics in multi-domain Escherichia coli methionyl-tRNA synthetase (Ec MetRS). In particular, a comparative study was carried out to evaluate the effectiveness of coarse-grained normal mode analysis and all-atom molecular dynamic simulation in predicting pre-existing pathways of inter-domain communications in this enzyme. Integration of dynamic information of residues with their evolutionary features (conserved and coevolved) demonstrated that multiple residue-residue interaction networks exist in Ec MetRS that promote dynamic coupling between the anticodon binding domain and the connective polypeptide I domain, which are > 50Å apart, through correlated motions. Mutation of residues on these pathways have distinct impact on the dynamics and function of this enzyme. Moreover, the present study revealed that the dynamic information obtained from the coarse-grained normal mode analysis is comparable to the atomistic molecular dynamics simulations in predicting the interaction networks that are essential for promoting coupled-domain dynamics in Ec MetRS.