STAT3 structure.

<p>Protein Data Bank (ID 1BG1) structure of STAT3 is shown. The structure has four domains: a N-terminal four-helix bundle (in blue, residues 138–320), an eight-stranded -barrel (in purple, residues 321–465), an -helical connector domain (in green, residues 466–585), and a SH2 domain (in yellow, residues 586 to 688).</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

Root mean square fluctuations.

<p>Root mean square fluctuation (RMSF) of the 12 peptidomimetics in complex with the SH2 domain of STAT3 is shown. Each RMSF value was computed using 1000 conformations of the peptidomimetic derived from the 10 ns molecular dynamics trajectory.</p

Hydrogen bond occupancy.

<p>Hydrogen bond occupancy plots for each peptidomimetic are shown. In each sub-plot, the x-axis represents the serial numbers of the residues of the SH2 domain of STAT3 and the y-axis represents the hydrogen bond occupancy value for a given residue. Hydrogen bond occupancy is computed as the fraction of conformations out of 1000 conformations of a peptidomimetic in which the given residue participates in a hydrogen bond. The 1000 conformations of each peptidomimetic were derived from the corresponding 10 ns molecular dynamics trajectory. Note that a hydrogen bond is ignored if it is present in less than 500 conformations.</p

Bent binding mode.

<p>The bent binding mode of peptidomimetic comp70 (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 comp70 is 190 nM.</p

Representative conformations after clustering.

<p>For each peptidomimetic, 5 conformations in complex with the SH2 domain (in gray) of STAT3 are shown. The 5 conformations are the representatives of the 5 clusters obtained after k-means clustering of the 1000 conformations that were derived from 10 ns molecular dynamics trajectory of each peptidomimetic-SH2 domain complex. IC₅₀ value represents the experimental binding affinity of each peptidomimetic derived using fluorescence polarization and N represents the number of rotatable bonds in each peptidomimetic.</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

Residues involved in hydrogen bonds.

<p>The residues (labeled) of the SH2 domain that form hydrogen bonds with at least one of the 12 peptidomimetics are shown. The top figure shows a cartoon representation of the SH2 domain and the bottom figure shows a surface representation. The surface coloring shows the Coulombic electrostatic potential in different regions of the surface of the SH2 domain. The potential ranges from positive (in blue) to negative (in red). Note that a hydrogen bond is ignored if it is present in less than 50% of the conformations in the 10 ns molecular dynamics trajectory.</p

12 peptidomimetics.

<p>2-D chemical representations of the 12 peptidomimetics that form our dataset are shown. IC₅₀ value represents the experimental binding affinity of each peptidomimetic derived using fluorescence polarization and N represents the number of rotatable bonds in each peptidomimetic.</p

Extended binding mode.

<p>The extended binding mode of peptidomimetic comp134 (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 comp134 is 83 nM.</p