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The coordinates of two solution-state NMR structures (mPrP 118–231 determined at 37 °C and pH of 4.5 [PDB entry: 2L39, model 1 (111 (link))] and Syrian hamster prion protein 89 to 230 [mouse residue numbering] determined at 30 °C and pH of 5.2 [PDB entry: 2PRP, superseded by 1B10, model 6 (112 (link))]) were used to build mPrP models denoted as WT-72-I and WT-72-II, respectively (Table S3). To obtain model WT-72-I, a sequence mPrP 72 to −117 was added to the former structure 2L39 using the Biovia Discovery Studio Visualizer (Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017: Dassault Systèmes, 2016). The 2PRP structure was used specifically to obtain a WT-72-II conformation without direct interactions between regions 72 and 120 and the C-terminal part of helix H3. To achieve this, we added a sequence mPrP 72 to 88 and made residue substitutions (i.e., hamster PrP -> mPrP) in the 89 to 230 part using the Biovia Discovery Studio Viewer. Mutations required to obtain the corresponding S3-72-I and S3-72-II constructs (28 (link)) were as described previously (68 ). Cbl coordinates were uploaded from the PDB (entry: 2BB5). After adding hydrogens where necessary, all the systems were prepared for simulations. Systems were solvated in 155 mM NaCl to approximate the composition of the cell medium.