During
protein synthesis, aminoacyl-
tRNA synthetases covalently link
amino acids with their cognate tRNAs.
Amino acid mutations in
glycyl-tRNA synthetase can disrupt
protein synthesis and lead to a
neurological disorder known as
Charcot-Marie-Tooth disease type 2D (CMT-2D). Several studies employing diverse techniques have identified potential disease mechanisms at the molecular level. The majority of CMT-2D mutations in glycyl-
tRNA are found within its dimer interface. However, no atomic structures bearing these mutations have been solved. Consequently, the specific disease-causing structural changes that occur in
glycyl-tRNA synthetase have not been definitively established. Here we use molecular dynamics simulations to probe conformational changes in
glycyl-tRNA synthetase caused by one mutation within the dimer interface: G240R. Our results show that the mutation alters the number of native interactions at the dimer interface and also leads to altered dynamics of two regions of
glycyl-tRNA synthetase associated with
tRNA binding. Additionally, we use our simulations to make predictions about the effects of other clinically reported CMT-2D mutations. Our results identify a region of the
glycyl-tRNA synthetase structure that may be disrupted in a large number of CMT-2D mutations. Structural changes in this region may be a common molecular mechanism in
glycyl-tRNA synthetase CMT-2D pathologies. Statement of significance: In this study, we use molecular dynamics simulations to elucidate structural conformations accessible to
glycyl-tRNA synthetase (GlyRS), an
enzyme that ligates cytosolic
glycine with
tRNA-Gly. This
protein contains multiple flexible regions with dynamics that elude in vitro structural characterization. Our computational approach provides unparalleled atomistic details of structural changes in GlyRS that contribute to its role in
protein synthesis. A number of mutations in GlyRS are associated with a peripheral nerve disorder,
Charcot-Marie-Tooth disease type 2D (CMT-2D). Mutation-induced structural and dynamic changes in GlyRS have similarity that elude in vitro structural characterization. Our simulations provide insights into disease mechanisms for one such mutation: G240R. Additionally, we leverage our computational data to identify regions of GlyRS critical to its function and to predict the effects of other disease-associated mutations. These results open up new directions for research into the molecular characterization of GlyRS and into hypothesis-driven studies of CMT-2D disease mechanisms.