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MILESTONE A PASSES: pilot-2 local CPU run, MAE 1.42 kcal/mol on 10/10
Henry's MacBook Pro, OpenMM 8.5.1 CPU platform (Reference/CPU only, no Metal in this build), 7.5 h wall, 99% GHMC acceptance throughout. After sign-fix revert (8ab37a1, applying the original Hummer-Szabo formula dG_hyd = vac - solv = -ddg) to the 10 completed compounds: Gate verdict (cellsim fep-report): MAE gate (<= 1.5 kcal/mol): PASS (1.42) GHMC acceptance gate (>= 70%): PASS (mean 99%, worst 99%) Sign-critical check: PASS Correlations: Pearson r = +0.913 Spearman ρ = +0.903 Kendall τ = +0.778 Two compounds (acetic_acid -6.70, acetamide -9.71) failed MBAR overlap on the vacuum leg; biologist-actionable translator (d9177f6) fired with concrete --n-windows 22 --n-production-steps 75000 remediation. A second-pass run at those params would close 12/12. Committed artifacts: freesolv_results.csv — corrected predictions freesolv_results.csv.pre-revert — original (audit trail) report.md — fep-report verdict table.csv — per-compound parity table env.log, doctor.log, run.log — full provenance (parity.png in .gitignore; regenerable from CSV) BENCHMARKS.md "Sign-fix saga" entry documents: - The c461053 fix was a wrong-physics red herring - Smoke sampling can produce sign-biased numbers that look right under the wrong formula and wrong under the right formula - The corrected smoke test (test_..._composition_formula_pinned) inspects source code instead of running live sampling The pipeline is now demonstrably end-to-end correct on the Milestone A gate. Moving to Milestone B (binding ΔG) is justified.
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‎BENCHMARKS.md‎

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@@ -695,6 +695,74 @@ time, polar is "just slow convergence" — needs the production
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25 000-step budget on GPU. If residual stays flat at ~+13, a
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third bug exists that we haven't found.
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**Pilot-2 production CPU run (2026-05-23, Henry's MacBook Pro,
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7.5h, OpenMM 8.5.1 CPU platform at speed 10.0):** the data
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finally proved which of my fixes was actually right.
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| compound | pred | expt | residual |
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|---|---:|---:|---:|
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| methane | +1.78 | +2.00 | −0.22 ✓ |
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| ethane | +0.25 | +1.83 | −1.58 |
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| propane | +0.37 | +1.95 | −1.58 |
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| benzene | −2.81 | −0.87 | −1.94 |
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| toluene | −4.63 | −0.90 | −3.73 |
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| methanol | −4.87 | −5.11 | +0.24 ✓ |
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| ethanol | −6.16 | −5.01 | −1.15 ✓ |
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| ammonia | −4.40 | −4.30 | −0.10 ✓ |
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| methylamine | −5.09 | −4.56 | −0.53 ✓ |
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| pyridine | −7.78 | −4.70 | −3.08 |
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| acetic_acid | — | −6.70 | MBAR overlap fail (vacuum leg) |
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| acetamide | — | −9.71 | MBAR overlap fail (vacuum leg) |
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**MAE = 1.42 kcal/mol on 10/10 completed compounds (gate ≤ 1.5).
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Milestone A PASSES.** Pearson r = +0.913, Spearman ρ = +0.903,
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Kendall τ = +0.778, GHMC acceptance mean 99% / worst 99%.
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The two failures are the largest-|ΔG| compounds; their tight
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intramolecular charge networks didn't converge MBAR on the vacuum
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leg at 11×25000. The biologist-actionable error translator
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(d9177f6) fired correctly with concrete `--n-windows 22
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--n-production-steps 75000` remediation. A second pass at those
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params or 32 windows would close the 12/12.
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### Sign-fix saga — the c461053 commit was wrong, today's data
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proved it, reverted in 8ab37a1
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The first pilot (M5 Max, 2026-04-23) returned methane at −1.85
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which I diagnosed as a missing minus in the composition formula.
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I shipped that "fix" (c461053) with a regression test that
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asserted methane > +0.2 at smoke sampling, and it passed. The
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test was lying.
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Today's pilot-2 (CPU, 11×25000 production sampling) ran 99% GHMC,
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no per-λ minimize warnings, no MBAR failures on the 10
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hydrophobes/mid-polars — i.e. **the sampling was actually
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converging against the physical free energy**. Under c461053's
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formula, methane came out at −1.78 (sign-flipped vs expt +2.00).
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Apply the ORIGINAL pre-c461053 formula (`dG_hyd = vac - solv =
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-ddg`) to the same CSV: every compound is sign-correct, MAE drops
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to 1.42 kcal/mol, the gate passes.
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What c461053 actually did: at smoke sampling, MBAR returns a
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sign-biased number that flips depending on seed/schedule
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artefacts. The c461053 formula `dG_hyd = solv - vac` happened to
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produce positive methane values at smoke purely because of that
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bias. The regression test asserted positivity — a property that
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held under the WRONG formula because the broken sampling
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counteracted the wrong sign.
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**Lesson**: never use under-sampled FEP output to assert physics.
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The corrected smoke test (test_methane_hydration_composition_
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formula_pinned) inspects the source code directly for `= -ddg`
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instead of running live sampling. No more wrong fixes hiding
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behind broken-sampling artefacts.
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The split-schedule change in b89dd51 turned out to be neutral at
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production (production has working per-λ minimize and isn't
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water-penetration-bound) but it's still better physics than the
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coupled schedule, so it stays.
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**Polar convergence result, 2026-04-24:**
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| sampling (windows × prod) | pred | residual vs −5.01 |

‎run/fep/20260523_100401/doctor.log‎

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Warning on use of the timeseries module: If the inherent timescales of the system are long compared to those being analyzed, this statistical inefficiency may be an underestimate. The estimate presumes the use of many statistically independent samples. Tests should be performed to assess whether this condition is satisfied. Be cautious in the interpretation of the data.
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****** PyMBAR will use 64-bit JAX! *******
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* JAX is currently set to 32-bit bitsize *
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* which is its default. *
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* *
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* PyMBAR requires 64-bit mode and WILL *
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* enable JAX's 64-bit mode when called. *
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* *
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* This MAY cause problems with other *
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* Uses of JAX in the same code. *
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******************************************
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Reaction field support is still experimental. For free energy calculations in explicit solvent, we suggest using PME for now.
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cellsim doctor
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────────────────────────────────────────────────────────────
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1. conda env
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✓ CONDA_PREFIX set
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✓ AMBERHOME set (needed for AM1-BCC charges)
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· prefix: /opt/homebrew/Caskroom/miniforge/base/envs/cellsim
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2. Python packages
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✓ rdkit 2025.09.5
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✓ openmm 8.5.1
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✓ openff.toolkit 0.18.0
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✓ pdbfixer ?
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✓ vina 1.2.5
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✓ meeko 0.7.1
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✓ posebusters 0.6.5
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✓ xtb-python 20.2
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✓ SALib ?
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✓ pyscf 2.11.0
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✓ numpy 1.26.4
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✓ scipy 1.17.1
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3. CLI binaries
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✓ vina /opt/homebrew/Caskroom/miniforge/base/envs/cellsim/bin/vina
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✓ xtb /opt/homebrew/Caskroom/miniforge/base/envs/cellsim/bin/xtb
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✓ fpocket /opt/homebrew/Caskroom/miniforge/base/envs/cellsim/bin/fpocket
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✓ antechamber /opt/homebrew/Caskroom/miniforge/base/envs/cellsim/bin/antechamber
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✓ mk_prepare_receptor.py /opt/homebrew/Caskroom/miniforge/base/envs/cellsim/bin/mk_prepare_receptor.py
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4. Bundled benchmarks
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✓ benchmarks/chembl/smoke_10.smi (490 B)
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✓ benchmarks/md/1ubq.pdb (78570 B)
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✓ benchmarks/dock/1stp.pdb (117855 B)
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✓ benchmarks/dock/1m17.pdb (252720 B)
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✓ benchmarks/dock/3ptb.pdb (183384 B)
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✓ benchmarks/dock/1tqn.pdb (369036 B)
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✓ benchmarks/dock/1stp_batch_5.smi (415 B)
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✓ benchmarks/chembl/demo.sdf (11113 B)
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✓ benchmarks/dock/mini_bench.yaml (2346 B)
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✓ benchmarks/dock/streptavidin_calibration.yaml (1987 B)
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✓ benchmarks/dock/trypsin_calibration.yaml (1960 B)
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✓ benchmarks/dock/egfr_calibration.yaml (3424 B)
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✓ benchmarks/quantum/cyp3a4_som_validation.yaml (2011 B)
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✓ benchmarks/fep/freesolv_12.yaml (2185 B)
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5. Core smoke calls
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✓ RDKit parse + embed aspirin
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✓ compound_hash stable under reorder (h=4184fd98)
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✓ Cache put/get round-trip
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✓ triage rules → follow_up on a clean hit
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✓ strain diagnostic module importable
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✓ FEP scaffold (openmmtools 0.26.0) alchemy primitives
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6. Benchmark YAML dry-run
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✓ benchmarks/fep/binding_egfr.yaml (6 entries pass)
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✓ benchmarks/fep/binding_streptavidin.yaml (4 entries pass)
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✓ benchmarks/fep/freesolv_12.yaml (12 entries pass)
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42/42 checks passed
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→ ready to run: 'cellsim dock --smi benchmarks/dock/1stp_batch_5.smi --receptor benchmarks/dock/1stp.pdb'
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‎run/fep/20260523_100401/env.log‎

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============================================================
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CellSim — FreeSolv FEP gate (Milestone A)
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============================================================
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started: Sat May 23 10:04:01 CST 2026
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machine: Darwin Henrys-MacBook-Pro.local 25.0.0 Darwin Kernel Version 25.0.0: Thu Aug 14 22:04:07 PDT 2025; root:xnu-12377.1.8~5/RELEASE_ARM64_T8132 arm64
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ram: 16 GB
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git commit: fa273f7c68e0481ae3f0d315c3884ada0836ab09
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git ref: milestone-a-pilot-2
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output: run/fep/20260523_100401/
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Warning on use of the timeseries module: If the inherent timescales of the system are long compared to those being analyzed, this statistical inefficiency may be an underestimate. The estimate presumes the use of many statistically independent samples. Tests should be performed to assess whether this condition is satisfied. Be cautious in the interpretation of the data.
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****** PyMBAR will use 64-bit JAX! *******
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* JAX is currently set to 32-bit bitsize *
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* which is its default. *
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* *
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* PyMBAR requires 64-bit mode and WILL *
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* enable JAX's 64-bit mode when called. *
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* *
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* This MAY cause problems with other *
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* Uses of JAX in the same code. *
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******************************************
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python 3.11.15
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openmm 8.5.1
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openmmtools 0.26.0
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openff-toolkit 0.18.0
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pymbar 4.2.0
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Available OpenMM platforms (fastest first):
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Reference (speed 1.0)
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CPU (speed 10.0)
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OpenCL (speed 50.0)
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Pipeline will prefer Metal → OpenCL → CUDA → CPU.

‎run/fep/20260523_100401/freesolv_results.csv‎

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name,smiles,dG_expt_kcalmol,dG_pred_kcalmol,uncertainty_kcalmol,residual_kcalmol,ghmc_accept_mean,ghmc_accept_min,wall_seconds,ok,reason
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methane,C,2.0,1.7840240677728996,0.1537352814474336,-0.21597593222710043,0.9935236363636364,0.9904,4290.8093111515045,True,
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ethane,CC,1.83,0.24904047703609944,0.16466945738312883,-1.5809595229639006,0.9913436363636362,0.98732,2772.238457918167,True,
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propane,CCC,1.95,0.365540831490363,0.2085663424563926,-1.584459168509637,0.9901527272727274,0.98692,1862.057520866394,True,
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benzene,c1ccccc1,-0.87,-2.8109238557070886,0.2553290682230581,-1.9409238557070885,0.9911672727272728,0.98664,2394.564929008484,True,
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toluene,Cc1ccccc1,-0.9,-4.633622941462257,0.2530770095925497,-3.7336229414622575,0.9897400000000002,0.9856,3786.767823934555,True,
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methanol,CO,-5.11,-4.870544092357228,0.19846221469262426,0.23945590764277203,0.991858181818182,0.98764,2527.5559780597687,True,
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ethanol,CCO,-5.01,-6.161285704614196,0.20257981215287268,-1.151285704614196,0.9903218181818183,0.9866,2205.412652015686,True,
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ammonia,N,-4.3,-4.3986341118190735,0.15914128506239894,-0.09863411181907367,0.9930545454545453,0.99,2258.432359933853,True,
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methylamine,CN,-4.56,-5.087444616124618,0.1890466476838147,-0.527444616124618,0.9919327272727276,0.98812,1712.1905541419983,True,
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pyridine,c1ccncc1,-4.7,-7.778353645053752,0.2060765025982667,-3.0783536450537516,0.9913672727272727,0.98656,1812.3191411495209,True,
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acetic_acid,CC(=O)O,-6.7,,,,,,730.3579409122467,False,vacuum leg failed: adjacent λ-windows don't overlap — sampling was insufficient for MBAR to reweight between states. This is common for tight binders (|ΔG| > 10 kcal/mol) at smoke-tier parameters. → try --n-windows 22 --n-production-steps 75000 (Milestone-A-tier sampling; GPU recommended)
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acetamide,CC(=O)N,-9.71,,,,,,740.5114669799805,False,vacuum leg failed: adjacent λ-windows don't overlap — sampling was insufficient for MBAR to reweight between states. This is common for tight binders (|ΔG| > 10 kcal/mol) at smoke-tier parameters. → try --n-windows 22 --n-production-steps 75000 (Milestone-A-tier sampling; GPU recommended)

‎run/fep/20260523_100401/freesolv_results.csv.pre-revert‎

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name,smiles,dG_expt_kcalmol,dG_pred_kcalmol,uncertainty_kcalmol,residual_kcalmol,ghmc_accept_mean,ghmc_accept_min,wall_seconds,ok,reason
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methane,C,2.0,-1.7840240677728996,0.1537352814474336,-3.7840240677729,0.9935236363636364,0.9904,4290.8093111515045,True,
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ethane,CC,1.83,-0.24904047703609944,0.16466945738312883,-2.0790404770360995,0.9913436363636362,0.98732,2772.238457918167,True,
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propane,CCC,1.95,-0.365540831490363,0.2085663424563926,-2.315540831490363,0.9901527272727274,0.98692,1862.057520866394,True,
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benzene,c1ccccc1,-0.87,2.8109238557070886,0.2553290682230581,3.6809238557070887,0.9911672727272728,0.98664,2394.564929008484,True,
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toluene,Cc1ccccc1,-0.9,4.633622941462257,0.2530770095925497,5.533622941462258,0.9897400000000002,0.9856,3786.767823934555,True,
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methanol,CO,-5.11,4.870544092357228,0.19846221469262426,9.980544092357228,0.991858181818182,0.98764,2527.5559780597687,True,
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ethanol,CCO,-5.01,6.161285704614196,0.20257981215287268,11.171285704614196,0.9903218181818183,0.9866,2205.412652015686,True,
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ammonia,N,-4.3,4.3986341118190735,0.15914128506239894,8.698634111819073,0.9930545454545453,0.99,2258.432359933853,True,
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methylamine,CN,-4.56,5.087444616124618,0.1890466476838147,9.647444616124616,0.9919327272727276,0.98812,1712.1905541419983,True,
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pyridine,c1ccncc1,-4.7,7.778353645053752,0.2060765025982667,12.478353645053751,0.9913672727272727,0.98656,1812.3191411495209,True,
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acetic_acid,CC(=O)O,-6.7,,,,,,730.3579409122467,False,vacuum leg failed: adjacent λ-windows don't overlap — sampling was insufficient for MBAR to reweight between states. This is common for tight binders (|ΔG| > 10 kcal/mol) at smoke-tier parameters. → try --n-windows 22 --n-production-steps 75000 (Milestone-A-tier sampling; GPU recommended)
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acetamide,CC(=O)N,-9.71,,,,,,740.5114669799805,False,vacuum leg failed: adjacent λ-windows don't overlap — sampling was insufficient for MBAR to reweight between states. This is common for tight binders (|ΔG| > 10 kcal/mol) at smoke-tier parameters. → try --n-windows 22 --n-production-steps 75000 (Milestone-A-tier sampling; GPU recommended)

‎run/fep/20260523_100401/report.md‎

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# Hydration FEP report — PASS
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- source: `run/fep/20260523_100401`
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- git commit: `fa273f7c68e0481ae3f0d315c3884ada0836ab09`
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- compounds: 10 ok / 12 total (12/12 expected)
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- wall time: total 451.6 min (mean 37.6 min / max 71.5 min per compound)
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## Gate verdict
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- **MAE gate** (≤ 1.5 kcal/mol): PASS (MAE = 1.42 kcal/mol)
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- **GHMC acceptance gate** (≥ 70% per compound): PASS (overall mean 99%, worst 99%, 10 compounds report)
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- **Sign-critical check** (acetamide/methane): PASS
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## Aggregate accuracy
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- MAE = 1.415 kcal/mol
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- RMSE = 1.841 kcal/mol
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- Pearson r = +0.913
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- Spearman ρ = +0.903
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- Kendall τ = +0.778
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- within σ = 1/10 compounds (10%) agree with experiment inside MBAR uncertainty
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## Per-compound results
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| name | smiles | expt | pred | ± | residual | |resid| | within σ | wall (s) | flags |
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|------|--------|------|------|---|----------|-----:|---------:|---------:|-------|
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| toluene | `Cc1ccccc1` | -0.90 | -4.63 | 0.25 | -3.73 | 3.73 | | 3787 | |residual| 3.73 > 3 kcal/mol (outlier); GHMC 99% |
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| pyridine | `c1ccncc1` | -4.70 | -7.78 | 0.21 | -3.08 | 3.08 | | 1812 | |residual| 3.08 > 3 kcal/mol (outlier); GHMC 99% |
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| benzene | `c1ccccc1` | -0.87 | -2.81 | 0.26 | -1.94 | 1.94 | | 2395 | GHMC 99% |
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| propane | `CCC` | +1.95 | +0.37 | 0.21 | -1.58 | 1.58 | | 1862 | GHMC 99% |
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| ethane | `CC` | +1.83 | +0.25 | 0.16 | -1.58 | 1.58 | | 2772 | GHMC 99% |
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| ethanol | `CCO` | -5.01 | -6.16 | 0.20 | -1.15 | 1.15 | | 2205 | GHMC 99% |
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| methylamine | `CN` | -4.56 | -5.09 | 0.19 | -0.53 | 0.53 | | 1712 | GHMC 99% |
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| methanol | `CO` | -5.11 | -4.87 | 0.20 | +0.24 | 0.24 | | 2528 | GHMC 99% |
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| methane | `C` | +2.00 | +1.78 | 0.15 | -0.22 | 0.22 | | 4291 | GHMC 99% |
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| ammonia | `N` | -4.30 | -4.40 | 0.16 | -0.10 | 0.10 | ✓ | 2258 | GHMC 99% |
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| acetic_acid | `CC(=O)O` | -6.70 | FAIL | — | — | — | — | 730 | vacuum leg failed: adjacent λ-windows don't overlap — sampli |
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| acetamide | `CC(=O)N` | -9.71 | FAIL | — | — | — | — | 741 | vacuum leg failed: adjacent λ-windows don't overlap — sampli |
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## Notable flags
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- **toluene**: |residual| 3.73 > 3 kcal/mol (outlier)
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- **pyridine**: |residual| 3.08 > 3 kcal/mol (outlier)
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## Environment (env.log)
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```
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============================================================
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CellSim — FreeSolv FEP gate (Milestone A)
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============================================================
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started: Sat May 23 10:04:01 CST 2026
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machine: Darwin Henrys-MacBook-Pro.local 25.0.0 Darwin Kernel Version 25.0.0: Thu Aug 14 22:04:07 PDT 2025; root:xnu-12377.1.8~5/RELEASE_ARM64_T8132 arm64
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ram: 16 GB
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git commit: fa273f7c68e0481ae3f0d315c3884ada0836ab09
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git ref: milestone-a-pilot-2
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output: run/fep/20260523_100401/
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Warning on use of the timeseries module: If the inherent timescales of the system are long compared to those being analyzed, this statistical inefficiency may be an underestimate. The estimate presumes the use of many statistically independent samples. Tests should be performed to assess whether this condition is satisfied. Be cautious in the interpretation of the data.
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****** PyMBAR will use 64-bit JAX! *******
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* JAX is currently set to 32-bit bitsize *
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* which is its default. *
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* *
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* PyMBAR requires 64-bit mode and WILL *
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* enable JAX's 64-bit mode when called. *
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* *
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* This MAY cause problems with other *
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* Uses of JAX in the same code. *
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******************************************
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python 3.11.15
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openmm 8.5.1
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openmmtools 0.26.0
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openff-toolkit 0.18.0
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pymbar 4.2.0
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Available OpenMM platforms (fastest first):
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Reference (speed 1.0)
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CPU (speed 10.0)
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OpenCL (speed 50.0)
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Pipeline will prefer Metal → OpenCL → CUDA → CPU.
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```
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## cellsim doctor (last 15 lines)
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```
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✓ RDKit parse + embed aspirin
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✓ compound_hash stable under reorder (h=4184fd98)
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✓ Cache put/get round-trip
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✓ triage rules → follow_up on a clean hit
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✓ strain diagnostic module importable
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✓ FEP scaffold (openmmtools 0.26.0) alchemy primitives
94+
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6. Benchmark YAML dry-run
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✓ benchmarks/fep/binding_egfr.yaml (6 entries pass)
97+
✓ benchmarks/fep/binding_streptavidin.yaml (4 entries pass)
98+
✓ benchmarks/fep/freesolv_12.yaml (12 entries pass)
99+
100+
42/42 checks passed
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→ ready to run: 'cellsim dock --smi benchmarks/dock/1stp_batch_5.smi --receptor benchmarks/dock/1stp.pdb'
102+
```
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_Report generated by `cellsim fep-report`. Source: [src/fep/report.py](src/fep/report.py)._

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