Figure 3.

Forced unbinding profile of UDP. To elucidate the effect of a single point mutation of the arginine residue (Arg255) of GPR17, potentially involved in nucleotide binding, simulations of the forced unbinding of UDP from the wild type (WT) and the mutant (R255I) receptor models are compared. Panel a shows the pulling energy developed to unbind UDP from WT (in magenta) and from R255I (in black). The detected significant difference in energy peak intensities suggests that the mutation actually affects the binding of UDP. The distances between the couples of atoms involved in the formation of hydrogen/electrostatic bonds occurring between the ligand and either WT or R255I receptors are reported in panels b and c. In the case of WT, for almost the whole duration of the simulation, residue Arg255 holds the ligand near the pocket, thus allowing UDP to maintain interactions with other residues, among which are Tyrl85, Tyr251, and Tyr262 (b). The same interactions are loosen up at the early stages of simulation in R255I receptor (c). In panel d, some representative frames of the unbinding pathway of UDP (red sticks) from GPR17 (blue cartoon) are reported.