Multiple Pathways Promote Dynamical Coupling between
Catalytic Domains in <i>Escherichia coli</i> Prolyl-tRNA
Synthetase
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Abstract
Aminoacyl-tRNA synthetases are multidomain
enzymes that catalyze
covalent attachment of amino acids to their cognate tRNA. Cross-talk
between functional domains is a prerequisite for this process. In
this study, we investigate the molecular mechanism of site-to-site
communication in <i>Escherichia coli</i> prolyl-tRNA synthetase
(Ec ProRS). Earlier studies have demonstrated that evolutionarily
conserved and/or co-evolved residues that are engaged in correlated
motion are critical for the propagation of functional conformational
changes from one site to another in modular proteins. Here, molecular
simulation and bioinformatics-based analysis were performed to identify
dynamically coupled and evolutionarily constrained residues that form
contiguous pathways of residue–residue interactions between
the aminoacylation and editing domains of Ec ProRS. The results of
this study suggest that multiple pathways exist between these two
domains to maintain the dynamic coupling essential for enzyme function.
Moreover, residues in these interaction networks are generally highly
conserved. Site-directed changes of on-pathway residues have a significant
impact on enzyme function and dynamics, suggesting that any perturbation
along these pathways disrupts the native residue–residue interactions
that are required for effective communication between the two functional
domains. Free energy analysis revealed that communication between
residues within a pathway and cross-talk between pathways are important
for coordinating functions of different domains of Ec ProRS for efficient
catalysis