🧬 Experiments D77 – D111

Spectral Protein Structure Analysis

IBP-ENM: a single spectral decomposition of the protein contact network simultaneously yields domain boundaries, hinge locations, and per-residue structural roles — without any training data.

78%

Domain k-accuracy
(36 proteins)

ρ = 0.779

Single-state dynamics
prediction

4.49×

Allosteric site
enrichment

100%

Archetype
classification (12/12)

The Method: IBP-ENM

Identity-Based Programming – Elastic Network Model. Start with a protein's 3D structure from the PDB. Build the contact network (residues within ~8Å). Compute the graph Laplacian. Decompose its spectrum.

The Fiedler vector (second-smallest eigenvector) naturally bisects the protein at its weakest structural connection — this is the domain boundary. Recursive spectral clustering with silhouette-based k-selection determines how many domains the protein has, automatically. No training data. No sequence alignment. Just the contact geometry. The "identity" in IBP: a protein's structural identity is what survives when you disturb it.

Beyond domains, the full spectrum encodes vibrational modes, hinge dynamics, and per-residue structural importance. The core insight from IBP: the cutting protocol itself identifies the protein. How the spectrum responds to disturbance reveals the protein's structural archetype.

The Discovery Timeline

D82: Domain Detection Benchmark

Silhouette-Based k-Selection · 36 Proteins

Silhouette-based k-selection on NJW-normalized spectral embeddings determines the number of protein domains with 78% accuracy — a 7× improvement over the eigengap heuristic (11%). Validated against CATH ground truth on 36 multi-domain proteins plus 12 single-domain controls (zero false positives).

Silhouette k-accuracy: 28/36 = 78%
Eigengap k-accuracy: 4/36 = 11%
Statistical significance: p = 2.85×10⁻⁶ (Wilcoxon)
When k is correct: mean ARI = 0.641 = oracle (identical)

D92: Single-State Dynamics Prediction

Predicting Motion from a Single Snapshot

Can we predict how much a protein can move from just one structure? D90 showed the spectral gap λ₂/λ₃ is a near-invariant across conformational states: ρ = +0.779, p = 0.0006.

This transforms IBP from "a tool that compares two structures" to "a tool that predicts dynamics from one structure." 12 features extracted from a single spectral decomposition — spectral gap, domain asymmetry, hinge fraction, spectral entropy, Fiedler range — are combined into a leave-one-out cross-validated predictor.

Gap conservation: ρ(gap_A, gap_B) = +0.779, p = 0.0006
The spectrum "remembers" dynamics even from a single snapshot.

D96: Allosteric Site Detection

Spectral Surgery Finds Real Biology

"Spectral surgery" iteratively removes contacts and observes how the spectral gap responds. "Lock" contacts — whose removal maximally drops the gap — cluster at domain boundaries (11× enrichment) and bridge edges (30×+ enrichment in T4 lysozyme/DHFR).

But is this biologically meaningful, or graph-theory talking to itself? Fisher's exact test against known functional sites (active sites, hinges, allosteric sites, mutation hotspots) validates the signal:

Allosteric enrichment: 4.49×
Verdict: "VALIDATED: algebra finds real biology"
The algebraically important residues are the biologically important ones.

D109: The Thermodynamic Band

7 Fano-Mapped Instruments · 83% Accuracy

The eigenvalue spectrum λ₁...λₙ encodes the full vibrational partition function: entropy S_vib, heat capacity C_v, Helmholtz free energy F, and mode localization (IPR). Using this, we classify proteins into structural archetypes.

7 independent disturbance modes — explicitly mapped to Fano points using the semantic labels from D38 (DOING, FEELING, KNOWING, etc.):

Instrument	Semantic Label	What It Probes
Algebraic	DOING	Max \|Δgap\| — symmetry breaking
Musical	FEELING	Max mode scatter — resonance
Fick	KNOWING	Fick-balanced — diffusion
Thermal	BEING	Max ΔS_vib — entropy
Cooperative	WANTING	Max \|Δβ\| — cooperativity
Propagative	RELATING	Max spatial radius — allosteric reach
Fragile	BECOMING	High B-factor edges — thermal soft spots

D108 baseline: 17% accuracy (2/12)
D109 thermodynamic band: 83% accuracy (10/12)
Same Fano structure that organizes music also classifies protein archetypes.

D110: The Enzyme Lens

Asymmetric Entropy Detector · 92% Accuracy

D109 missed two enzyme_active proteins — T4 lysozyme and DHFR — predicting them as allosteric. The gap was tiny: DHFR scored allosteric 0.258 vs enzyme 0.240 (Δ = 0.018).

Enzymes have localized active-site dynamics (high IPR in low modes), while allosteric proteins show delocalized signal propagation. An "enzyme lens" based on IPR and asymmetric entropy redistribution fixes DHFR:

D109 → D110: 83% → 92% accuracy (11/12)
Sole remaining miss: T4 lysozyme — a "hinge enzyme" whose catalytic cleft sits at the domain boundary.

D111: Multi-Mode Hinge Detection ⭐

Modes 2–5 Reveal Hidden Dynamics · 100% Accuracy

T4 lysozyme looks allosteric in mode 1 — its IPR is 0.0165 (threshold: 0.025), well below the enzyme cutoff. But modes 2–5 tell a different story. Higher-mode amplitude still concentrates at the catalytic cleft.

The key observable: hinge occupation ratio (hinge_R₂₋₅). Enzymes show hinge_R > 1.0 — higher modes amplify the catalytic hinge. Allosteric proteins show hinge_R ≤ 1.0 — mode 1 exhausts the hinge. T4 lysozyme: hinge_R = 1.091 (enzyme). AdK: hinge_R = 0.952 (allosteric). One number, one clean physical story.

D110 → D111: 92% → 100% accuracy (12/12)
Progression: 17% (D108) → 83% (D109) → 92% (D110) → 100% (D111)
Zero regressions: all 11 previously-correct proteins remain correct.
5/5 enzyme, 2/2 barrel, 3/3 allosteric/dumbbell/globin. 0 false barrel.

The full framework is formalized as the ibp_enm Python package — 11 modules, 50 passing tests, clean public API.

Validation Against Ground Truth

Everything here is benchmarked against established structural biology databases:

CATH

Domain boundaries and domain count (k). Our 78% k-accuracy is measured against CATH classifications for 36 multi-domain proteins.

DynDom

Hinge residues and conformational changes across paired structures. Used for dynamics prediction validation.

PDB / UniProt

Functional site annotations, B-factors, active site locations. Fisher's exact test validates spectral surgery against annotated residues.

Software & Visualizations

The framework is implemented as ibp_enm — a Python package with 11 modules (thermodynamics, carving, archetypes, instruments, synthesis, band) and 50 passing tests. The synthesis pipeline progresses from MetaFickBalancer → EnzymeLensSynthesis → HingeLensSynthesis, each layer adding a post-hoc lens for finer-grained classification.

Jupyter notebooks include protein B-factor correlation plots benchmarked against 200 PDB structures, spectral gap conservation plots across conformational pairs, and domain boundary overlays on 3D protein structures.

Source code: github.com/Earthform-AI/ibp-enm

Connections to Other Threads

Composable Algebra

The 8-layer architecture that the 7 Fano-mapped instruments emerge from

🎵

Fano Music

D109's "Musical" instrument was named for D38's semantic Fano labels

Algebraic Repair

Spectral surgery and repair both search for structure-preserving transforms — one on protein graphs, the other on video frames

This thread comprises experiments D77 – D111 of the CAExperiments project. Source code: github.com/Earthform-AI/ibp-enm. Join our Discord to discuss the structural biology work, or leave your email for updates.