Fig. 5: Results of mixed-solvent MD simulations. | Communications Chemistry

Fig. 5: Results of mixed-solvent MD simulations.

From: Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97

Fig. 5

The 10 hit fragments of Table 1 were simulated, including both enantiomers of TROLL2 and TROLL7. a Binding-site residue map. Grey rectangles specify amino acids along the primary sequence (horizontal axis) which are in the vicinity (<6 Å from the dummy atom) of the two sites with highest occupancies of the corresponding fragment. b Relative propensity of observed binding interactions. The bars indicate in how many of the 12 individual simulations the residue was identified as binding-site residue according to panel a, using the color code of panel c. c Pie chart with the distribution of the two sites with highest occupancy for each fragment across the N-domain surface (N = 24). d Location of the corresponding regions on the surface, color-coded according to the pie chart. e Illustration of fragments for which a binding mode could be postulated from the mixed-solvent simulations: i TROLL2 and ii TROLL7 in the SHP II site; iii TROLL8 in a cavity near the SHP binding region (SHP III); and iv TROLL12 in SHP II, in a different orientation compared to TROLL2 and TROLL7. A representative pose in stick representation as well as the occupancies of selected heavy atoms in mesh representation are shown. The poses were selected as described in the Materials and Methods section.

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