Extended Data Fig. 7: Conformational flexibility of Neo-2/15 in molecular dynamics simulations. | Nature

Extended Data Fig. 7: Conformational flexibility of Neo-2/15 in molecular dynamics simulations.

From: De novo design of potent and selective mimics of IL-2 and IL-15

Extended Data Fig. 7

a, Molecular dynamics simulations started from the computational model of Neo-2/15 (top) converged into structures similar to the crystal conformation. Apo Neo-2/15 is shown in red thick tubes (chain A from PDB ID: 6GD6) and 45 (randomly selected) molecular dynamics conformations from 5 independent simulations are shown in thin grey tubes. Bottom, the plot shows the r.m.s.d. along 5 independent simulations (average r.m.s.d. = 1.93 Å). b, Similar to a, but for (control) molecular dynamics simulations started from the crystallographic structure of human IL-2. Top, crystal conformation of human IL-2 (chain A from PDB ID: 2B5I) is shown in blue thick tubes and 45 (randomly selected) conformations from 5 independent molecular dynamics simulations are shown in thin grey tubes (average r.m.s.d. = 2.02 Å). c, Top, similar to a and b, but showing molecular dynamics structures for simulations started from the computational model of Neo-2/15 bound to human IL-2Rβγc. The plot shows the r.m.s.d. along 5 independent molecular dynamics simulations (average r.m.s.d. to apo Neo-2/15 (model) = 1.28 Å). The lower structure shows the nearest conformation (to the apo Neo-2/15 computational model) that was sampled on each of the 5 independent simulations (structures from the first 50 ns of molecular dynamics simulations were not considered). Bottom, a 2D scatter plot (and the underlying density plot, in which yellow, blue, green and purple represent decreasing densities) comparing the r.m.s.d. (after discarding the first 50 ns of each simulation) for apo Neo-2/15 (computational model) versus the r.m.s.d. for the holo crystal structure of Neo-2/15 (in complex with the mouse receptor). The conformations sampled by Neo-2/15 when in complex with human IL-2Rβγc are more similar to the apo Neo-2/15 structure (computational model) than to the Neo-2/15 conformation observed in complex with mouse IL-2Rβγc. d, As in c, but for molecular dynamics simulations started from the computational model of apo Neo-2/15 in complex with the crystallographic structure of mouse IL-2Rβγc. The model of apo Neo-2/15 was generated by aligning (using TMalign) the ternary computational model of Neo-2/15 with human IL-2Rβγc (from c) into our crystallographic structure of mouse IL-2Rβγc (PDB ID: 6GD5) (average r.m.s.d. to holo Neo-2/15 (mouse) = 1.43 Å). Bottom, 2D scatter plot (and the underlying density plot, in which yellow, blue, green and purple represent decreasing densities) comparing the r.m.s.d. (after discarding the first 50 ns of molecular dynamics simulation) for apo Neo-2/15 (computational model) versus the r.m.s.d. for the holo crystal structure of Neo-2/15 (in complex with the mouse receptor). Unlike in c, the conformations sampled by Neo-2/15 when in complex with mouse IL-2Rβγc are more similar to the Neo-2/15 conformation observed in the crystallographic structure of the ternary complex of Neo-2/15 with mouse IL-2Rβγc (Fig. 3). For clarity, all the r.m.s.d. plots were filtered (running average filter, 5 frames = 100 ps), and points in the 2D scatter plots were subsampled every 25 conformations (that is, every 500 ps); however, the density plot corresponds to all the analysed conformations (that is, the last 40 ns of 5 molecular dynamics simulations that were analysed, and conformations were recorded each 20 ps).