| |
| """Warhead-to-E3 span distribution from the water ensembles. |
| |
| Per frame, the distance between the centroid of the warhead core (the group that |
| occupies the target pocket) and the centroid of the E3 ligand core. In a |
| productive ternary complex that span has to bridge the two pockets, so the |
| distribution shows which separations a linker can hold. Water, not chloroform: |
| the ternary complex forms in the cytosol. |
| |
| This is a description of reach, not a degradation score; scoring it needs a |
| target ternary geometry from docking. Replica spread is printed alongside so |
| poorly converged runs are visible. |
| |
| Default SMARTS are for the EGFR-VHL series (anilinoquinazoline warhead, |
| 4-hydroxyproline E3 anchor); override with --warhead-smarts / --e3-smarts. |
| |
| Usage: |
| python ternary_span.py egfrvhl_rank4 ms39_ref --out span.png |
| """ |
| import argparse, glob, os |
| import numpy as np |
| import mdtraj as md |
| from rdkit import Chem |
| from scipy.stats import gaussian_kde |
| import matplotlib; matplotlib.use("Agg") |
| import matplotlib.pyplot as plt |
|
|
| WH_SMARTS = "c1cc2ncncc2cc1" |
| E3_SMARTS = "[#6]1[#6][#6](O)[#6][#7]1" |
|
|
|
|
| def anchors(sdf, wh_smarts, e3_smarts): |
| m = Chem.MolFromMolFile(sdf, removeHs=False) |
| wh = list(m.GetSubstructMatch(Chem.MolFromSmarts(wh_smarts))) |
| e3 = list(m.GetSubstructMatch(Chem.MolFromSmarts(e3_smarts))) |
| syms = [a.GetSymbol() for a in m.GetAtoms()] |
| return wh, e3, syms |
|
|
|
|
| def spans_for_run(run, solvent, wh_smarts, e3_smarts): |
| """Per-replica span arrays (A), or None if the run can't be used.""" |
| name = os.path.basename(run.rstrip("/")) |
| tops = glob.glob(os.path.join(run, solvent, "*_solvated.pdb")) |
| dcds = sorted(glob.glob(os.path.join(run, solvent, "rep*", f"{name}_prod.dcd"))) |
| if not tops or not dcds: |
| print(f"{name:14s} no {solvent} data") |
| return None |
| wh, e3, sdf_syms = anchors(os.path.join(run, f"{name}.sdf"), wh_smarts, e3_smarts) |
| if not wh or not e3: |
| print(f"{name:14s} SMARTS match failed (wh={len(wh)} e3={len(e3)})") |
| return None |
| out = [] |
| for d in dcds: |
| tr = md.load(d, top=tops[0]) |
| lig = [a.index for r in tr.topology.residues |
| if not r.is_water and r.n_atoms > 5 for a in r.atoms] |
| sub = tr.atom_slice(lig) |
| if [a.element.symbol for a in sub.topology.atoms] != sdf_syms: |
| print(f"{name:14s} SDF/MD atom-order mismatch, skipping") |
| return None |
| xyz = sub.xyz * 10.0 |
| out.append(np.linalg.norm(xyz[:, wh, :].mean(1) - xyz[:, e3, :].mean(1), axis=1)) |
| return out |
|
|
|
|
| def main(): |
| ap = argparse.ArgumentParser() |
| ap.add_argument("runs", nargs="+", help="run directories, one per compound") |
| ap.add_argument("--solvent", default="water") |
| ap.add_argument("--warhead-smarts", default=WH_SMARTS) |
| ap.add_argument("--e3-smarts", default=E3_SMARTS) |
| ap.add_argument("--out", default="ternary_span.png") |
| a = ap.parse_args() |
|
|
| fig, ax = plt.subplots(figsize=(11, 6.5), dpi=150) |
| fig.patch.set_facecolor("white") |
| cmap = plt.get_cmap("viridis") |
| print(f"{'compound':14s}{'mean span':>10s}{'sd':>6s}{'min':>6s}{'max':>6s}" |
| f"{'range':>7s}{'rep spread':>12s}") |
| print("-" * 67) |
| drawn = 0 |
| for i, run in enumerate(a.runs): |
| label = os.path.basename(run.rstrip("/")) |
| per_rep = spans_for_run(run, a.solvent, a.warhead_smarts, a.e3_smarts) |
| if not per_rep: |
| continue |
| s = np.concatenate(per_rep) |
| spread = float(np.std([r.mean() for r in per_rep])) |
| print(f"{label:14s}{s.mean():10.1f}{s.std():6.1f}{s.min():6.1f}" |
| f"{s.max():6.1f}{s.max()-s.min():7.1f}{spread:12.1f}") |
| grid = np.linspace(3, 25, 300) |
| ax.plot(grid, gaussian_kde(s, bw_method=0.15)(grid), lw=2.2, |
| color=cmap(i / max(1, len(a.runs) - 1)), |
| label=f"{label} ({s.mean():.0f} A)") |
| drawn += 1 |
| if not drawn: |
| return |
| ax.set_xlabel("warhead to E3 pharmacophore separation (A)") |
| ax.set_ylabel("probability density") |
| ax.set_title("Warhead to E3 span\n" |
| f"centroid distance between the pocket-binding groups ({a.solvent})", |
| fontsize=12.5, weight="bold", loc="left") |
| ax.legend(fontsize=8.5, frameon=False, ncol=2) |
| ax.grid(alpha=0.25) |
| fig.tight_layout() |
| fig.savefig(a.out, facecolor="white") |
| print(f"\nwrote {a.out}") |
|
|
|
|
| if __name__ == "__main__": |
| main() |
|
|
