Savytskyi O. Computational modeling of molecular dynamics simulations of H. sapiens tyrosyl-tRNA synthetase and its mutant forms

In this work we constructed the model of the full-length HsTyrRS 3D structure and studied its conformational mobility by all-atom molecular dynamics simulations. MD simulations of the full length HsTyrRS have shown that the binding of C-terminal modules to mini-TyrRS catalytic dimer is highly asymmetric in terms of the interface structure and dynamics. Strong hydrogen bonding between the R93 residue of the ELR cytokine motif and A340 and E479 residues of C-module was observed in MD simulations. These data support the idea that the full length HsTyrRS lacks its cytokine activity due to the interaction between N- and C-terminal modules, which protect the ELR cytokine motif.In this work the 3D structures of G41R, E196K and 153-156delVKQV HsTyrRS mutants have been modelled. Long 100 ns MD simulations of G41R and 153-156delVKQV mutants of HsTyrRS revealed significant changes of their conformational dynamics. In general, mutant proteins revealed less relaxed states with higher values of root-mean square fluctuations. Analysis of spatial contacts between 2 monomers in enzyme revealed the expanse dimer interface in HsTyrRS. The melting of H9 helix (T141-A148) and subsequent partial melting of H11 helix were observed in 153-156delVKQV mutant of TyrRS. A novel b-sheet formation was observed in K147-E157 region (monomer A) in G41R mutant for 20-100 ns and in K146-E151 region (monomer B) in 153-156delVKQV mutant for 5-65 ns time interval of MD simulation in CP1 region of Rossmann fold. Our results support the idea, that defects of the intermolecular interfaces in the complexes of mutational forms of HsTyrRS with cognate tRNA(Tyr) and/or eEF1A2 may be common molecular mechanism of Charcot-Marie-Tooth disorder.