Plot of active dofs for expert (A) and auto (B) experiments.

<p>Color bar indicates cumulative per-residue torsional change over the entire determined transition. The two experiments show comparable activity in torsional dofs, largely confined to central loops through which much of the bending occurs.</p

Plots of total angular change for each residue over the determined transition.

<p>(A) Central hinge only. (B) Hinge+flex region. (C) Automatic. (D) shows active residues explicitly used in planning for hinge (red), hinge+flex (green) and automatic (blue) runs.</p

Comparison of the final state of the reverse transition (blue) and the direct transition (red).

<p>Structures are nearly identical save for a 10 residue relaxation of a loop region in the balancing interface. Both transitions come to within 1Å of their goal.</p

Example of a structured schema for an arbitrary molecule.

<p>Subsets of dofs are defined, along with the associated weighting (shown here as percentages) defining the relative probability of selection. Though this example is non-overlapping and hierarchical, any combination of possibly non-contiguous subsets are allowed in our implementation. In this example, a move is generically requested, and subsequently sampled probabilistically from the set containing all loop regions in the top (blue) region of the structure. The yellow circles represent possible moves.</p

Comparison of a computationally identified intermediate state and nmr structure pdb:2H25.

<p>The identified intermediate state (dark blue) corresponds to the centroid of the low energy region shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068826#pone-0068826-g007" target="_blank">Figure 7</a>. The nmr structure is known to be close to the semi-closed conformation of mbp, showing excellent agreement at the resolution of the ensemble. The closest state along a direct transition between known open and bound forms (aqua structure) of mbp to pdb:2H25 shows almost perfect agreement with the centroid structure.</p

Plots of angular change in dofs for hinge (A), hinge+flex (B) and auto (C) experiments.

<p>Residues are colored by absolute total angular change, with blue indicating a small change and red a large change. Hinge and Flex (A, B) experiments show relatively low activity outside of the planning regions. The automatically guided experiment (C) shows high activity in the hinge and -sheet regions of both subdomains.</p

pca landscape of all conformations generated in the mbp experiments.

<p>Each point represents a unique conformation. The color indicates energy with darker colors representing more energetically stable states. The red path shows the path found with the default schema, starting from the open state with the bound state as the goal. The green path represents the reverse case, with the default schema, starting at the bound state and moving toward the open state. The purple path was produced using the expert- schema, moving from the bound state towards the open state. The yellow star indicates the position of a known nmr structure (pdb:2H25) of the semi-closed state. The aqua star indicates the centroid conformation of the energetic valley between the open and bound states and falls extremely close to all paths, as well as the nmr structure. The circular pattern in the green path was automatically generated and seems to arise from a slight bending reversal that occurs near the semi-closed state.</p

Correlation between experimental and esimated affinities.

<p>The top figure shows the variation of the Pearson correlation coefficient (R), computed between the experimental binding affinities and the estimated binding affinities of the 12 peptidomimetics, with the length of molecular dynamics simulation. The binding affinities were estimated using 4 different schemes. and represent non-entropic contribution to the binding affinity computed using the MMGBSA and MMPBSA methods in AmberTools software package. represents the entropic contribution computed using the <i>nmode</i> method in AmberTools. The bottom figure shows, for each peptidomimetic, the estimated binding affinity value computed using scheme. Because the values computed using MMGBSA, MMPBSA, and nmode methods are averaged over the snapshots of the molecular dynamics trajectory, we also plot the variation of estimated binding affinity values with increasing length of the molecular dynamics simulation.</p

Energies as calculated by the Amber99 forcefield for a typical automatically guided run.

<p>All experiments produced similar plots. Energies are plotted against the transition coordinate (the amount of progress between start and goal for the transition). (A) Amber energies for the raw output of the automatically guided run (B) Amber energies after 100 rounds of minimization (C) Distance between raw output and minimized structure. All structures are determined to be of low energy, post-minimization, according to the Amber forcefield, with only mild (much less than 0.1Å full-atom rmsd) differences between the two structures.</p

Wedged binding mode.

<p>The proposed novel wedged binding mode of peptidomimetic comp121 (in green) is shown. The peptidomimetic is in complex with the SH2 domain of STAT3 which is shown in cartoon (top) and surface (bottom) representations. The residues of the SH2 domain which participate in hydrogen bonds are labeled. The top figure also shows the hydrogen bonds (dashed lines) that the residues (in yellow) participate in. The surface coloring shows the Coulombic electrostatic potential in the different regions of the surface of the SH2 domain. The potential ranges from positive (in blue) to negative (in red). The IC₅₀ value for comp121 is 68 nM.</p