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Release: Milestone A FreeSolv gate ready for M5 Max handoff
Wires OpenMM Metal / OpenCL platform preference into sampling.py (falls back CPU if neither available). Rewrites scripts/run_freesolv_m5max.sh as a self-contained production- parameter runner: doctor check → 11 windows × 50 ps production × 2 legs × 12 compounds → tarball + macOS notification. Adds HANDOFF.md as the definitive friend-facing instructions (prerequisites, run, what to send back, what Henry wants in the CSV, troubleshooting). This is the first tagged release intended for external compute.
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‎HANDOFF.md‎

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# CellSim FEP Handoff — Apple-silicon Mac runner
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You are running CellSim's Milestone A accuracy gate on behalf of
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a friend. This is one command, ~4–6 hours wall time on an M5 Max,
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and produces one tarball to send back.
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This README is written for you **and** your Claude Code. Either
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can follow it; Claude will probably run it end-to-end with minimal
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human intervention.
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## What you're running
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Absolute hydration free energy (ΔG_hyd) of 12 small molecules
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using alchemical free-energy perturbation (FEP). The 12 molecules
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span +2.0 kcal/mol (methane, hydrophobic) to −9.7 kcal/mol
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(acetamide, hydrophilic).
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**Target**: predicted ΔG_hyd within 1.5 kcal/mol MAE of the
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published FreeSolv experimental values.
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The pipeline is:
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`SMILES → OpenFF Sage 2.1.0 + AM1-BCC charges → OpenMM TIP3P
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solvated System → openmmtools alchemical decoupling →
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MCMC sampling with GHMC integrator + MBAR free-energy estimate`
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## Hardware requirements
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- **Apple silicon Mac** (M1/M2/M3/M4/M5, any Pro/Max/Ultra
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variant). Intel Mac also works but slower.
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- **32 GB RAM recommended**, 16 GB will work but may swap.
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- **~5 GB free disk** in the CellSim repo (data + output).
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- **Plugged in**, display-sleep OK but full-sleep NOT OK.
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Set before running:
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```bash
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sudo pmset -c disablesleep 1
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```
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Re-enable after:
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```bash
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sudo pmset -c disablesleep 0
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```
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## One-time setup (first run only)
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1. Install mamba/miniforge if you don't have it:
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```bash
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brew install miniforge
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```
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2. Clone the release:
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```bash
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git clone https://github.com/Rockman6/CellSim-3D-Multicellular-Biology-Drug-Testing-Simulator.git CellSim
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cd CellSim
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git checkout <release-tag> # Henry will tell you which tag
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```
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3. Create the conda environment:
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```bash
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mamba env create -f environment.yml
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conda activate cellsim
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```
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This installs ~60 packages and takes 10–20 minutes.
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4. Install `terminal-notifier` so the script can ping you when
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it finishes:
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```bash
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brew install terminal-notifier
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```
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5. Verify the install:
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```bash
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./scripts/cellsim doctor
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```
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You should see "**39/39 checks passed**". If fewer pass, send
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Henry the output — do **not** proceed.
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## The run
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One command:
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```bash
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./scripts/run_freesolv_m5max.sh
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```
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The script will:
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1. Activate the `cellsim` conda env.
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2. Print the OpenMM platform list (Metal / OpenCL / CPU) so you
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can see which backend is used.
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3. Run `cellsim doctor` and abort if it fails.
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4. Execute the 12-compound FreeSolv gate at production parameters:
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- 11 alchemical windows per leg
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- 50 ps equilibration + 50 ps production per window
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- 100 samples per window (2 ps stride)
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- 2 legs per compound (vacuum + TIP3P-solvated)
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- = ~2.2 ns simulated MD per compound × 12 = 26 ns total
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5. Write everything to `run/fep/<timestamp>/` and bundle into
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`freesolv_m5max_<timestamp>.tar.gz`.
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6. Fire a macOS notification ("CellSim FreeSolv FEP: PASS/FAIL")
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when complete.
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Expected wall time:
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- **M5 Max (40-core GPU)**: 4–6 hours
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- **M2/M3 Max**: 6–9 hours
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- **M1 Pro/Max**: 8–12 hours
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- **Intel Mac (CPU only)**: 24–48 hours — not recommended
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You can close the Terminal window during the run — the process
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continues. Use `tail -f run/fep/*/run.log` in another Terminal to
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watch progress.
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## What to send back
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When the script finishes, send **one file**:
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```
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freesolv_m5max_<timestamp>.tar.gz
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```
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(in the CellSim repo root). Send via:
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- **WeChat file transfer** (works for files up to ~100 MB; tarball
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will be ~1–5 MB)
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- **AirDrop** (if you're close geographically)
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- **Email / Google Drive / Dropbox**
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- **GitHub Gist** (if public data is OK — it is; FreeSolv
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numbers are public benchmark data)
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The tarball contains:
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| File | What it is | Why Henry wants it |
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|---|---|---|
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| `env.log` | OpenMM/Python/platform versions | Reproducibility — must match exactly |
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| `doctor.log` | cellsim doctor output | Catches env drift between machines |
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| `run.log` | Full pipeline stdout | Contains per-compound ΔG, per-window GHMC acceptance, wall times, any NaN warnings |
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| `freesolv_results.csv` | 12-row CSV of predictions | The numbers Henry analyses |
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## What Henry specifically wants in the CSV
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Each row of `freesolv_results.csv` has:
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```
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name, smiles, dG_expt_kcalmol, dG_pred_kcalmol, uncertainty_kcalmol,
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residual_kcalmol, wall_seconds, ok, reason
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```
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Specifically he'll compute:
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- **MAE** = mean |residual| across all 12 → gate is ≤ 1.5 kcal/mol.
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- **Per-compound sign correctness** — methane should give ≈ +2 kcal/mol
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(positive), not −2 (negative); the CPU pilot gave −2 due to
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under-sampling, so seeing it flip to positive on M5 Max is the
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load-bearing finding.
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- **GHMC acceptance rate** — must be ≥ 70% per window (≥ 75%
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preferred). Low acceptance means the ΔG is unreliable.
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- **Wall time per compound** — tells Henry the M5 Max throughput
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so he can plan the next round (EGFR kinase relative FEP).
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## Troubleshooting
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### `cellsim doctor` fails
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Copy the terminal output, send it to Henry. Do NOT try to fix it.
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### Script errors immediately with "python: command not found"
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You didn't activate the env. Run:
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```bash
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conda activate cellsim
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```
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### Script errors with "Particle coordinate is NaN"
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**Send Henry the log anyway.** That failure mode is itself
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scientifically valuable. The CPU version sometimes hits this at
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shorter MD lengths; Henry needs to know if it shows up on
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M5 Max too or if longer sampling dissolves it.
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### Run times out after 6 hours and hasn't finished
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That's fine. Send the partial CSV — 6 of 12 compounds is better
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than nothing. Just append a line to the tarball note saying
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"killed at <time>, <N> of 12 compounds completed".
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### Machine overheats / fan roars / battery drains
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Normal for sustained GPU work. Machine is plugged in and
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physically safe. Continue.
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### You want to reduce the run to ~2 hours
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Edit `scripts/run_freesolv_m5max.sh`, change:
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```
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--production-steps 25000
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```
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to:
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```
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--production-steps 10000
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```
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This gives a less-converged result (still useful as a first pass).
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Tell Henry you used shorter production when you send the tarball.
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## What this actually tests (Henry's framing)
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The CellSim project got a long critique from Henry's professor
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about whether the simulator can actually replace wet-lab
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experiments — specifically whether "physics-derived priors" from
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FEP are good enough to build cell biology on top of. Methane
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hydration is the simplest FEP test: if we can't get methane right,
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nothing else matters.
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Your run is **the M5 Max-accessible test** of whether longer MD
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sampling dissolves the entropy-capture issue Henry saw on CPU.
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Professor threshold:
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- Acceptance ≥ 75%
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- ΔG_hyd(methane) = +2.0 ± 0.5 kcal/mol
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- Uncertainty < 0.6 kcal/mol
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Hit those and Milestone A clears, Campaign 2 (real cell biology)
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opens.
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## Questions
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Ask Henry directly. He will give Claude explicit instructions
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too — if your Claude is unsure about something, let it paste
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the question into WeChat to Henry and wait.
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Thanks for lending the machine. Good luck.

‎scripts/run_freesolv_m5max.sh‎

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#!/usr/bin/env bash
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# CellSim — Milestone A FreeSolv FEP gate runner for Apple-silicon Mac.
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# One command, walk away, come back to a tarball to send back to Henry.
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#
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# Target hardware: M1 Pro / Max / Ultra, M2, M3, M4, M5 Max. ≥ 32 GB
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# unified memory recommended; 16 GB works but may swap.
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#
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# Expected wall time (from CPU grid extrapolation + OpenCL 5× speedup):
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# - 4-6 hours on M5 Max
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# - 6-10 hours on M1/M2 base
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# Plugged in + display-sleep-only (not full sleep) required.
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#
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# The script runs the Milestone A gate per the professor's acceptance
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# criteria: all 12 FreeSolv compounds at production parameters
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# (50 ps equilibration + 50 ps production per window × 11 windows ×
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# 2 legs = ~2.2 ns simulated MD per compound). Emits:
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# - per-compound predicted ΔG_hyd with MBAR uncertainty
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# - per-compound per-window GHMC acceptance rates
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# - aggregate MAE vs experimental (FreeSolv gate: MAE ≤ 1.5 kcal/mol)
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set -euo pipefail
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if [ ! -f "benchmarks/fep/freesolv_12.yaml" ]; then
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echo "error: run from CellSim repo root (not $(pwd))" >&2
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exit 2
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fi
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# Activate env
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if ! command -v conda >/dev/null 2>&1; then
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echo "error: conda/mamba not found. Install miniforge first:" >&2
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echo " brew install miniforge" >&2
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exit 2
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fi
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source "$(conda info --base)/etc/profile.d/conda.sh"
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conda activate cellsim
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# Output dir, timestamped so repeat runs don't collide
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STAMP=$(date +%Y%m%d_%H%M%S)
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OUT_DIR="run/fep/${STAMP}"
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mkdir -p "${OUT_DIR}"
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echo "============================================================"
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echo "CellSim — FreeSolv FEP gate (Milestone A)"
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echo "============================================================"
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echo " started: $(date)"
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echo " machine: $(uname -a)"
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echo " ram: $(sysctl -n hw.memsize 2>/dev/null | awk '{print $1/1024/1024/1024 " GB"}' || echo '?')"
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echo " git commit: $(git rev-parse HEAD)"
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echo " git ref: $(git describe --tags --always 2>/dev/null || echo '?')"
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echo " output: ${OUT_DIR}/"
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echo ""
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# Env + platform report — critical for reproducibility
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python -c "
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import openmm, openmmtools, openff.toolkit, pymbar, sys
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from openmm import Platform
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print('python ', sys.version.split()[0])
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print('openmm ', openmm.__version__)
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print('openmmtools ', openmmtools.__version__)
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print('openff-toolkit', openff.toolkit.__version__)
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print('pymbar ', pymbar.__version__)
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print()
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print('Available OpenMM platforms (fastest first):')
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for i in range(Platform.getNumPlatforms()):
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p = Platform.getPlatform(i)
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print(f' {p.getName()} (speed {p.getSpeed()})')
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print()
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print('Pipeline will prefer Metal → OpenCL → CUDA → CPU.')
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" 2>&1 | tee "${OUT_DIR}/env.log"
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echo ""
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# Cellsim doctor — fail fast if env is broken
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echo "=== cellsim doctor ==="
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./scripts/cellsim doctor 2>&1 | tee "${OUT_DIR}/doctor.log" | tail -5
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DOCTOR_EXIT=${PIPESTATUS[0]}
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if [ $DOCTOR_EXIT -ne 0 ]; then
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echo "" >&2
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echo "error: cellsim doctor failed. Check ${OUT_DIR}/doctor.log" >&2
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echo "Do NOT proceed with the gate run until doctor passes." >&2
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exit 3
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fi
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echo ""
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# Run the full FreeSolv gate
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echo "=== FreeSolv FEP gate starting at $(date) ==="
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echo "Parameters: 11 windows × 25 000 production steps (50 ps at 2 fs)"
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echo " × 5 000 equilibration steps (10 ps)"
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echo " × 2 legs (vacuum + TIP3P-solvated)"
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echo " × 12 FreeSolv compounds (methane → acetamide)"
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echo ""
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time ./scripts/cellsim fep-freesolv \
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benchmarks/fep/freesolv_12.yaml \
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--n-windows 11 \
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--production-steps 25000 \
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--equilibration-steps 5000 \
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--sample-stride 250 \
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--out-csv "${OUT_DIR}/freesolv_results.csv" \
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2>&1 | tee "${OUT_DIR}/run.log"
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EXIT_CODE=${PIPESTATUS[0]}
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echo ""
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echo "============================================================"
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echo "Finished at $(date) (exit ${EXIT_CODE})"
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echo " 0 = MAE ≤ 1.5 kcal/mol (gate passed)"
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echo " non-0 = gate failed or some compounds NaN'd"
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echo "============================================================"
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echo ""
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ls -la "${OUT_DIR}/"
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echo ""
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# Bundle for transfer
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TARBALL="freesolv_m5max_${STAMP}.tar.gz"
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tar czf "${TARBALL}" -C run/fep "${STAMP}/"
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echo "Created: ${TARBALL} ($(du -h ${TARBALL} | cut -f1))"
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echo ""
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echo "Send this tarball back to Henry (WeChat / email / Google Drive /"
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echo "AirDrop). It contains the CSV, the env report, the doctor log, and"
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echo "the full stdout log — Henry will analyse locally."
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echo ""
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# Notify on completion (silent if terminal-notifier isn't installed)
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if command -v terminal-notifier >/dev/null 2>&1; then
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STATUS=$([ $EXIT_CODE -eq 0 ] && echo "PASS" || echo "FAIL")
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terminal-notifier \
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-title "CellSim FreeSolv FEP" \
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-subtitle "${STATUS} (exit ${EXIT_CODE})" \
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-message "Tarball ready: ${TARBALL}. Send it to Henry." \
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-sound Glass \
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-activate com.apple.Terminal 2>/dev/null || true
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fi
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exit ${EXIT_CODE}

‎src/fep/sampling.py‎

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@@ -94,10 +94,29 @@ def sample_alchemical_windows(
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Context as _Context,
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VerletIntegrator as Verlet,
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LocalEnergyMinimizer as _Min,
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Platform,
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)
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from openmmtools import mcmc, states
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from openmmtools import mcmc, states, cache
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from openmmtools.alchemy import AlchemicalState
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# Prefer the fastest available platform: Metal (Apple silicon
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# OpenMM 8.2+) → OpenCL (works on Apple silicon via Metal shim,
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# Intel, AMD, NVIDIA) → CUDA → CPU. On an M5 Max this gives a
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# ~5-10× speedup over CPU. openmmtools' context cache uses the
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# first platform available in its list unless we pin one.
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_preferred = ("Metal", "OpenCL", "CUDA", "CPU")
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_chosen_platform = None
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for _name in _preferred:
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try:
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_p = Platform.getPlatformByName(_name)
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cache.global_context_cache.platform = _p
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_chosen_platform = _name
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break
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except Exception:
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continue
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logger.info(
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"FEP sampling platform: %s", _chosen_platform or "default")
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t0 = time.time()
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schedule = _default_lambda_schedule(n_windows)
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result = AlchemicalSamplingResult(

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