In all panels, black lines refer to DEN refinements, whereas red lines refer to noDEN refinements. (a) Showing how the (γ, *w*_{DEN}) grid-search determines the values that give the best R_{free} value for the synthetic diffraction data set at d_{min}=4.5 Å. The R_{free} value is contoured using values calculated on a 6 × 5 grid (marked by small ‘+’ signs) where the parameter γ was [0.0, 0.2, 0.4, 0.06, 0.8, 1.0] and *w*_{DEN} was [3, 10, 30, 100, 300]. For each parameter pair we performed an extensive refinement protocol (). The contour plot shows clear minima and maxima with the value of R_{free} varying from 0.295 to 0.35. (b) Showing the contour map of the all-atom RMSD between the target structure 3app and the DEN-refined structure (repeat with the lowest R_{free} value) at each grid point in (a). Again there are clear minima and maxima with the RMSD varying from 1.47 to 1.60 Å. (c) Showing the R_{free} value as a function of d_{min} of the four synthetic diffraction data sets. Thick lines mark the lowest R_{free} values obtained from the ten repeats using the optimum parameters; the corresponding thin lines mark the highest R_{free} values. For the synthetic data sets at d_{min} ≥ 4 Å, DEN refinement performs much better than noDEN reaching lower R_{free} values. (d) Showing how Zemla’s GDT (<1 Å) score, which measures structural similarity to the target structure 3app, varies as a function of d_{min}; the dashed line indicates the GDT score of the initial model. At all resolutions, DEN out-performs noDEN and gives GDT values that are more favorable (higher) than those of the initial structure. (e) Showing how the RMSD of all atoms to the 3app target structure varies vs. d_{min} of the four synthetic diffraction data sets. Once again DEN gives lower RMSD values, especially at low-resolution. The DEN-refined models used in (d), and (e) correspond to the best models among ten repeats as assessed by R_{free} (black dots in panel (c)). Black ellipses indicate on the contour maps values corresponding to the structure with lowest R_{free} value obtained for d_{min}=4.5Å.

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