Home

CYPForge Wiki

CYPForge prepares cytochrome P450 (CYP450) protein–heme–ligand systems for Amber molecular dynamics. You give it a complex PDB and a ligand SDF; it returns a fully parameterized, solvated, ionized, and pre-equilibrated system that is ready to drop into a production MD script — together with a per-stage audit trail that says exactly what was done and why.

This wiki explains what CYPForge does, why the manual workflow it replaces is genuinely hard to get right, and how the math underneath the orchestrator keeps the assembly internally consistent.

Where to start

If you want…	Read
The motivation — why hand-stitching a CYP450 system is risky	Why CYPForge
The 10-stage workflow, three cores, and how the data flows	Architecture
The math behind heme placement, atom matching, and the consistency theorem	Mathematical Foundations
What changes between IC6, DIOXY, and CPDI heme states	Heme Parameterization
How the SDF → GAFF2 → RESP pipeline keeps atom identity safe	Ligand Parameterization
The PASS / WARN / FAIL discipline	Gate System and Manifests
Common errors and recovery	FAQ

In one sentence

CYPForge is a strict orchestration and audit shell for CYP450 Amber MD preprocessing — ten gated stages, JSON manifests, no guessing.

What CYPForge does not do

It does not run production MD. The final pre-MD stage is a 20 ns free NPT equilibration; everything beyond that is your downstream workflow. CYPForge's job is to make sure that what you feed into your production script is chemically and topologically correct, and that you have an audit trail to prove it.

Citations

CYPForge is an orchestration layer. The actual chemistry is done by Amber/AmberTools, PySCF (with GPU4PySCF), and Multiwfn; the bundled parameters come from Shahrokh et al. 2012. Cite everything you used:

Bundled heme parameters (IC6, DIOXY, CPDI under src/cypforge/data/heme_params/):

Shahrokh K, Orendt A, Yost GS, Cheatham TE III. Quantum mechanically derived AMBER-compatible heme parameters for various states of the cytochrome P450 catalytic cycle. J. Comput. Chem. 2012, 33(2): 119–133. doi:10.1002/jcc.21922

Amber MD engine (Core 3 pre-MD equilibration, pmemd / pmemd.cuda):

Case D.A. et al. Amber 2024, University of California, San Francisco, 2024.

Salomon-Ferrer R, Götz A.W, Poole D, Le Grand S, Walker R.C. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 2013, 9(9): 3878–3888. doi:10.1021/ct400314y

AmberTools (Antechamber + GAFF2 typing in Core 2):

Wang J, Wang W, Kollman P.A, Case D.A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 2006, 25(2): 247–260. doi:10.1016/j.jmgm.2005.12.005

Wang J, Wolf R.M, Caldwell J.W, Kollman P.A, Case D.A. Development and testing of a general amber force field. J. Comput. Chem. 2004, 25(9): 1157–1174. doi:10.1002/jcc.20035

PySCF / GPU4PySCF (HF/6-31G* wavefunction for the RESP step):

Sun Q. et al. PySCF: the Python-based simulations of chemistry framework. WIREs Comput. Mol. Sci. 2018, 8(1): e1340. doi:10.1002/wcms.1340

Sun Q. et al. Recent developments in the PySCF program package. J. Chem. Phys. 2020, 153(2): 024109. doi:10.1063/5.0006074

Multiwfn (ESP grid + two-stage RESP fit, Multiwfn_noGUI):

Lu T, Chen F. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33(5): 580–592. doi:10.1002/jcc.22885

Lu T. A comprehensive electron wavefunction analysis toolbox for chemists, Multiwfn. J. Chem. Phys. 2024, 161(8): 082503. doi:10.1063/5.0216272

RESP method (the charge model itself):

Bayly C.I, Cieplak P, Cornell W.D, Kollman P.A. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J. Phys. Chem. 1993, 97(40): 10269–10280. doi:10.1021/j100142a004

CYPForge itself: a manuscript is in preparation. Until then, cite the repository URL and the released tag (v1.3.0).

Full bundled-parameter provenance: src/cypforge/data/heme_params/PROVENANCE.json.