code/scripts/pxdesign_guidance/tds_pxdesign.py

"""
PXDesign + Twisted Diffusion Sampling (TDS).

Multi-round particle filtering with guided PXDesign:
  Round r:
    1. Generate N particles via PXDesign with Q_theta classifier guidance
    2. Score each particle with Q_theta selectivity margin
    3. Compute importance weights w_i ~ exp(margin_i / temperature)
    4. Resample particles (keep best, discard worst)
    5. Add perturbation noise for diversity

This combines in-process guidance (the "twisted proposal") with post-hoc
importance-weighted resampling for highest-quality designs.

Usage:
    python code/scripts/pxdesign_guidance/tds_pxdesign.py \
        --input experiments/pxdesign_cam/output/cam_binder.json \
        --qtheta_checkpoint results/checkpoints_cam_v3/best_phase2.pt \
        --ref_holo data/pdbs/cam_holo/3CLN.pdb \
        --ref_apo data/pdbs/cam_apo/1CFD.pdb \
        --n_particles 16 --n_rounds 4 \
        --guidance_scale 0.5 \
        --gpu 0
"""

import os
import sys
import argparse
import json
import logging
import shutil
import subprocess
from glob import glob

import numpy as np
import torch

logging.basicConfig(level=logging.INFO, format='%(asctime)s %(levelname)s %(message)s')
logger = logging.getLogger(__name__)

_SCRIPT_DIR = os.path.dirname(os.path.abspath(__file__))
_ALLO_CODE_DIR = os.path.abspath(os.path.join(_SCRIPT_DIR, '..', '..'))
_ALLO_ROOT = os.path.abspath(os.path.join(_ALLO_CODE_DIR, '..'))

if _ALLO_CODE_DIR not in sys.path:
    sys.path.insert(0, _ALLO_CODE_DIR)


def compute_ess(log_weights):
    """Compute effective sample size from log-weights."""
    log_weights = log_weights - log_weights.max()
    weights = np.exp(log_weights)
    weights = weights / weights.sum()
    return 1.0 / (weights ** 2).sum()


def run_guided_pxdesign_batch(input_json, outdir, n_sample, n_step,
                               gpu, guidance_args):
    """Run guided PXDesign as a subprocess."""
    pxdesign_python = 'python'
    cmd = [
        pxdesign_python,
        os.path.join(_SCRIPT_DIR, 'guided_pxdesign.py'),
        '--input', input_json,
        '--qtheta_checkpoint', guidance_args['checkpoint'],
        '--ref_holo', guidance_args['ref_holo'],
        '--ref_apo', guidance_args['ref_apo'],
        '--ref_chain', guidance_args['ref_chain'],
        '--guidance_scale', str(guidance_args['guidance_scale']),
        '--guidance_start', str(guidance_args.get('guidance_start', 0.8)),
        '--guidance_end', str(guidance_args.get('guidance_end', 0.1)),
        '--N_sample', str(n_sample),
        '--N_step', str(n_step),
        '--gpu', str(gpu),
        '--outdir', outdir,
    ]

    env = os.environ.copy()
    # Inherit CUDA_VISIBLE_DEVICES from parent

    logger.info(f"Running guided PXDesign: {n_sample} samples -> {outdir}")
    result = subprocess.run(cmd, capture_output=True, text=True, env=env,
                            timeout=7200)

    if result.returncode != 0:
        logger.error(f"PXDesign failed:\n{result.stderr[-2000:]}")
        return False
    return True


def run_vanilla_pxdesign_batch(input_json, outdir, n_sample, n_step, gpu):
    """Run vanilla PXDesign (no guidance) as a subprocess."""
    pxdesign_env = 'python'

    cmd = [
        pxdesign_env, '-m', 'pxdesign.runner.inference',
        '--dump_dir', outdir,
        '--input', input_json,
        '--dtype', 'bf16',
        '--N_sample', str(n_sample),
        '--N_step', str(n_step),
    ]

    env = os.environ.copy()
    # Inherit CUDA_VISIBLE_DEVICES from parent

    logger.info(f"Running vanilla PXDesign: {n_sample} samples -> {outdir}")
    result = subprocess.run(cmd, capture_output=True, text=True, env=env,
                            timeout=7200)

    if result.returncode != 0:
        logger.error(f"PXDesign failed:\n{result.stderr[-2000:]}")
        return False
    return True


def collect_pdbs(outdir):
    """Collect PDB/CIF paths from PXDesign output directory."""
    pdbs = []
    for ext in ('*.pdb', '*.cif'):
        pdbs.extend(glob(os.path.join(outdir, '**/' + ext), recursive=True))
    pdbs = sorted(pdbs)
    filtered = [p for p in pdbs if 'sample' in os.path.basename(p).lower()
                or 'design' in os.path.basename(p).lower()
                or 'rank' in os.path.basename(p).lower()]
    return filtered if filtered else pdbs


def tds_particle_filter(args):
    """Run TDS particle filtering with PXDesign."""
    from qtheta_pxdesign import QThetaPXDesignGuidance

    outdir = os.path.join(_ALLO_ROOT, args.outdir)
    os.makedirs(outdir, exist_ok=True)

    # Initialize scorer
    guidance = QThetaPXDesignGuidance(
        checkpoint=os.path.join(_ALLO_ROOT, args.qtheta_checkpoint),
        ref_holo=os.path.join(_ALLO_ROOT, args.ref_holo),
        ref_apo=os.path.join(_ALLO_ROOT, args.ref_apo),
        ref_chain=args.ref_chain,
        device=f'cuda:{args.gpu}',
    )
    guidance._lazy_init()

    guidance_args = {
        'checkpoint': args.qtheta_checkpoint,
        'ref_holo': args.ref_holo,
        'ref_apo': args.ref_apo,
        'ref_chain': args.ref_chain,
        'guidance_scale': args.guidance_scale,
        'guidance_start': args.guidance_start,
        'guidance_end': args.guidance_end,
    }

    all_designs = []
    round_summaries = []

    for round_idx in range(args.n_rounds):
        round_dir = os.path.join(outdir, f'round_{round_idx}')
        os.makedirs(round_dir, exist_ok=True)

        logger.info(f"\n{'='*60}")
        logger.info(f"TDS Round {round_idx + 1}/{args.n_rounds}")
        logger.info(f"{'='*60}")

        # Generate particles via guided PXDesign
        gen_dir = os.path.join(round_dir, 'generated')
        success = run_guided_pxdesign_batch(
            input_json=os.path.join(_ALLO_ROOT, args.input),
            outdir=gen_dir,
            n_sample=args.n_particles,
            n_step=args.N_step,
            gpu=args.gpu,
            guidance_args=guidance_args,
        )

        if not success:
            logger.warning(f"Round {round_idx} generation failed, skipping")
            continue

        # Collect and score particles
        pdbs = collect_pdbs(gen_dir)
        if not pdbs:
            logger.warning(f"No PDBs found in round {round_idx}")
            continue

        logger.info(f"Scoring {len(pdbs)} particles...")
        round_results = []
        for pdb_path in pdbs:
            result = guidance.score_design(pdb_path)
            if result is not None:
                result['pdb_path'] = pdb_path
                result['design_id'] = os.path.basename(pdb_path).replace('.pdb', '').replace('.cif', '')
                result['round'] = round_idx
                round_results.append(result)

        if not round_results:
            logger.warning(f"No scorable designs in round {round_idx}")
            continue

        margins = np.array([r['margin'] for r in round_results])

        # Compute importance weights
        log_weights = margins / args.temperature
        ess = compute_ess(log_weights)

        round_summary = {
            'round': round_idx,
            'n_particles': len(round_results),
            'margin_mean': float(margins.mean()),
            'margin_std': float(margins.std()),
            'margin_max': float(margins.max()),
            'frac_positive': float((margins > 0).mean()),
            'ess': float(ess),
        }
        round_summaries.append(round_summary)

        logger.info(f"Round {round_idx}: margin={margins.mean():.3f}±{margins.std():.3f}, "
                     f"max={margins.max():.3f}, S>0={round_summary['frac_positive']:.1%}, "
                     f"ESS={ess:.1f}/{len(round_results)}")

        # Add to design pool
        all_designs.extend(round_results)

        # Resample for next round (top-K selection for PXDesign since
        # we can't easily perturb and re-denoise)
        if round_idx < args.n_rounds - 1:
            # Copy best designs to inform next round
            # For PXDesign, each round generates fresh samples with guidance
            # Resampling influence is through the guidance strength
            # Increase guidance scale for later rounds
            guidance_args['guidance_scale'] = args.guidance_scale * (1.0 + 0.2 * (round_idx + 1))
            logger.info(f"Increasing guidance scale to {guidance_args['guidance_scale']:.2f} "
                        f"for next round")

    # Final summary
    if all_designs:
        all_designs.sort(key=lambda x: x['margin'], reverse=True)
        all_margins = np.array([d['margin'] for d in all_designs])
        holo_scores = np.array([d['q_holo'] for d in all_designs])

        # Best-of-K
        bok = {}
        for K in [1, 2, 5, 10]:
            n_trials = 2000
            n_avail = len(all_margins)
            successes = sum(
                1 for _ in range(n_trials)
                if all_margins[np.random.choice(n_avail, min(K, n_avail), replace=False)].max() > 0
            )
            bok[K] = successes / n_trials

        summary = {
            'method': 'PXDesign + TDS',
            'n_rounds': args.n_rounds,
            'n_particles_per_round': args.n_particles,
            'total_designs': len(all_designs),
            'guidance_scale': args.guidance_scale,
            'temperature': args.temperature,
            'margin_mean': float(all_margins.mean()),
            'margin_std': float(all_margins.std()),
            'margin_max': float(all_margins.max()),
            'frac_positive': float((all_margins > 0).mean()),
            'q_holo_mean': float(holo_scores.mean()),
            'best_of_k': {str(k): v for k, v in bok.items()},
            'round_summaries': round_summaries,
            'top5': all_designs[:5],
        }

        with open(os.path.join(outdir, 'tds_scores.json'), 'w') as f:
            json.dump(all_designs, f, indent=2)
        with open(os.path.join(outdir, 'tds_summary.json'), 'w') as f:
            json.dump(summary, f, indent=2)

        # Copy best designs to top-level
        best_dir = os.path.join(outdir, 'best_designs')
        os.makedirs(best_dir, exist_ok=True)
        for i, d in enumerate(all_designs[:20]):
            if os.path.exists(d['pdb_path']):
                dest = os.path.join(best_dir, f'rank_{i:02d}_{d["design_id"]}.pdb')
                shutil.copy2(d['pdb_path'], dest)

        logger.info(f"\n{'='*60}")
        logger.info(f"PXDesign + TDS Results ({len(all_designs)} total designs)")
        logger.info(f"  Margin: {all_margins.mean():.3f} ± {all_margins.std():.3f}")
        logger.info(f"  Max margin: {all_margins.max():.3f}")
        logger.info(f"  Fraction S > 0: {(all_margins > 0).mean():.1%}")
        logger.info(f"  Q(holo) mean: {holo_scores.mean():.3f}")
        logger.info(f"  Best-of-K:")
        for k, v in sorted(bok.items()):
            logger.info(f"    K={k:3d}: {v:.3f}")
        logger.info(f"{'='*60}")


def main():
    parser = argparse.ArgumentParser(description='PXDesign + TDS')
    parser.add_argument('--input', default='experiments/pxdesign_cam/output/cam_binder.json')
    parser.add_argument('--qtheta_checkpoint',
                        default='results/checkpoints_cam_v3/best_phase2.pt')
    parser.add_argument('--ref_holo', default='data/pdbs/cam_holo/3CLN.pdb')
    parser.add_argument('--ref_apo', default='data/pdbs/cam_apo/1CFD.pdb')
    parser.add_argument('--ref_chain', default='A')
    parser.add_argument('--n_particles', type=int, default=16,
                        help='Particles per round')
    parser.add_argument('--n_rounds', type=int, default=4,
                        help='Number of TDS rounds')
    parser.add_argument('--guidance_scale', type=float, default=0.5,
                        help='Initial guidance scale')
    parser.add_argument('--guidance_start', type=float, default=0.8)
    parser.add_argument('--guidance_end', type=float, default=0.1)
    parser.add_argument('--temperature', type=float, default=0.5,
                        help='Temperature for importance weights')
    parser.add_argument('--N_step', type=int, default=400)
    parser.add_argument('--gpu', type=int, default=0)
    parser.add_argument('--outdir', default='results/pxdesign_tds')
    args = parser.parse_args()

    tds_particle_filter(args)


if __name__ == '__main__':
    main()