Computational protocol: Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin

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Protocol publication

[…] Molecular docking and energy minimization experiments were performed using the MOE molecular modelling program 2015.10 and Yasara 15.11.18. The homology was built in the same procedure as used before. Chemical structures were created in ChemBioDraw Ultra14.0 (Perkin Elmer, Waltham, MA) and transferred to the MOE database. Ligands were then energy-minimized using the MMFF94 force field option with the restriction to preserve original chirality of the molecules and a root mean square deviation (RMSD) of 0.01 kcal/mol Å. The LowmodeMethod was used for conformation search in standard configuration (only D-penicillamine). Molecular docking examination was done with a molecular dynamics simulation in Yasara. The stereochemistry quality aspects of the resulting models were checked via the MOE program 2015.10. RMSD from starting to end conformation in the molecular dynamics calculation was estimated with MOE. The trajectory in the molecular dynamics calculation was analyzed with Yasara (modified scripts).The MOE docking protocols for rigid receptor and inducted fits were used in this study. The parameters for covalent docking were as follows: Experiment 1: reactant – D-penicillamine, functional group – alkylthiol, class – oxidation, product – disulfide; Experiment 2: reactant – MND, functional group – Michael acceptor, class – 1,4 addition, product – beta alkylether.Rigid receptor or inducted fit site and reactive site selected thiol refinement: GBVI/WSA dG scoring function.The optimal complex for each ligand and receptor was then subjected to MD using Yasara dynamics amber03 force field. A simulation cell was constructed around the hTTR covalent-bounded model (2*7.5 Å larger than the model) with a 7.9 Å real space cut-off for the electrostatic force calculated via the Particle Mesh Ewald method. The pKa values of the ionisable groups were predicted and assigned protonation states based on pH 7.4 (temperature = 298 K, density = 0.997). The cell was filled with water and the amber03 electrostatic potential was estimated at all water molecules, those with the lowest or highest potential was turned into sodium or chloride counter ions till the cell was neutral. A short steepest descent minimization was done to remove severe bumps followed by simulated annealing minimizations at 298 K. Molecular dynamics simulations were done with amber03 force field at 298 K and 0.9% NaCl in the simulation cell for 500 ps to refine the models. For further analysis simulation snapshots were captured every 25 ps over the simulation time from 30 ns. […]

Pipeline specifications

Software tools YASARA, YASARA Dynamics
Application Drug design
Organisms Caenorhabditis elegans, Homo sapiens
Chemicals Penicillamine, Vitamin K 3