10-13 November 2015
Villa Romanazzi Carducci
Europe/Rome timezone

Moldyngrid Virtual Laboratory as web-oriented grid-service for Biomolecular Simulations

Not scheduled
Villa Romanazzi Carducci

Villa Romanazzi Carducci

Via G. Capruzzi, 326 70124 Bari Italy


Oleksandr Savytskyi (Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine (IMBG of NAS of Ukraine))


Biomolecular simulations usually require vast computational resources and huge storage space for molecular dynamics (MD) trajectories. Recently, MolDynGrid virtual laboratory (http://moldyngrid.org) was established for interdisciplinary studies in computational structural biology and bioinformatics, especially for MD simulations of biological macromolecules and their complexes. Since 2013 VO moldyngrid became а part of the European Grid Infrastructure (EGI). All MD simulations were performed in GROMACS 4 package and NAMD 2.10, and some of trajectories were calculated with GPU acceleration. Besides the standard analysis tools provided by GROMACS and VMD packages, VL MolDynGrid has self-developed tools for MD analyses, і.е. Distributed Analyzer Script (DAS) and Pteros library (http://pteros.sourceforge.net) [1,2]. Currently, the MolDynGrid is being used for performing MD simulations of different proteins, such as tyrosyl-tRNA synthetase (TyrRS) and its mutant form G41R, which lead to Charcot-Marie-Tooth disease (degeneration of peripheral nerve fibers). Human TyrRS is the key enzyme of protein biosynthesis, which catalyzes the aminoacylation of tRNATyr. The full-length HsTyrRS does not reveal cytokine activity, but its proteolytic fragments reveal IL8-like activity of N-terminal catalytic module and EMAP II-like activity of non-catalytic C-terminal domain. Earlier, it was of proposed that the ELR-motif (E91, L92, R93) of TyrRS is responsible for IL8-like cytokine activity [Wakasugi et al, 1999], but the 3D structure of full-length human TyrRS is still unknown. In this work we have performed the modelling of full-length HsTyrRS structure and studied putative compactization by MD simulation. We observed the hydrogen bonding between R93 residue of the ELR motif and A340 and E479 residues of C-module in our MD simulations. This data support the idea that full-length TyrRS lacks its cytokine activity because of the interactions between N- and C-terminal modules, which protect the ELR cytokine motif [3-4]. Certain mutations in aminoacyl-tRNA synthetases lead to Charcot-Marie-Tooth disease (CMT) a group of heterogeneous inherited disorders that are characterized by degeneration of peripheral nerve fibers. G41R mutation in tyrosyl-tRNA synthetase is located at the active site and could block L-tyrosine binding (decrease >100-fold) in a similar way as G526R mutation in glycyl-tRNA synthetase blocks AMP moiety binding (Xie et al., 2006; Froelich et al., 2009). We observed the large patches (~20%) of positively charged area on the protein surfaces in the active sites both of G41R and G526R mutant enzymes. MD simulations showed the attraction of the chloride ion instead of potassium ion, which has functional role replacing the second lysine of the catalytic KMSKS-loop that affects the catalytic properties of human TyrRS. Our results confirm the similar effects for glycine mutations in both enzymes and propose the idea of conformational changes in the active site of human TyrRS after tyrosine and potassium/chloride binding.

Links, references, publications, etc.

[1] Salnikov A et al. Intl. J. Comp. 2010;9:294–300.
[2] Savytskyi OV et al. Proc. of the 6th IEEE Inter. Conference on IDAACS. 2011;1: 209–211
[3] Savytskyi OV et al. J Mol Recognit. 2013;26(2):113-20.
[4] Yesylevskyy SO Savytskyi et al. Biophys. Chem. 2011;154: 90–98.

Additional information

This work was partially supported by NAS of Ukraine Y2010-2015, FEBS Y2010-2014 and EGI Y2013-2015. Acknowledgments to Dr. T. Ferrari, Dr. M. Verlato, Dr. J. Walsh, Dr. E. Atanassov (VT GPGPU, EGI), Dr. D. Waldmann (EGCF and LRZ), Dr. S. Yesylevskyy (IOP) for technical support and useful discussions.

Supporting information may be found online http://onlinelibrary.wiley.com/doi/10.1002/jmr.2259/suppinfo

Primary author

Oleksandr Savytskyi (Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine (IMBG of NAS of Ukraine))

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