Understanding the dynamic behavior of wild-type and mutant LARS1 proteins: insight from comparative molecular dynamics simulations.

Abstract

Leucyl-tRNA synthetase 1 (LARS1) is a multi-domain enzyme essential for translational fidelity and amino acid sensing, with its anticodon-binding domain (ABD) playing a critical role in tRNA recognition. Missense variants in LARS1 have been associated with infantile liver failure syndrome type 1 (ILFS1), yet the structural mechanisms underlying their functional impact remain poorly understood. In this study, we investigated the structural and dynamical effects of the patient derived D794G mutation located in the anticodon-binding domain of LARS1. To evaluate its potential pathogenicity, comparative molecular dynamics (MD) simulations were performed for wild-type LARS1, the D794G variant, and the ClinVar-reported pathogenic variant Y835C. Structural analysis revealed that Asp794 contributes to a stabilizing interaction network involving hydrogen bonding with Tyr835 and aromatic stacking between Tyr835 and Phe797, linking adjacent α-helices within the ABD. Substitution with glycine abolished the Asp794-Tyr835 hydrogen bond and altered the local hydration and contact environment. Although RMSD and radius-of-gyration analyses indicated preservation of the global fold and compactness, RMSF, hydrogen-bond, SASA, contact, and principal-component analyses identified variant-dependent changes in local flexibility and conformational sampling, most prominently for D794G. These effects extend beyond the mutation site, suggesting propagation of structural perturbations to neighboring domains. Overall, these findings provide mechanistic insight into variant-associated changes in LARS1 structural dynamics and generate testable hypotheses regarding the importance of the 794-797-835 interaction network. The results highlight the importance of local interaction networks in maintaining domain stability and suggest that disruption of these interactions may have functional consequences.