HCLS AI Factory — Project Bible¶

Purpose: Complete implementation reference for building the HCLS AI Factory on NVIDIA DGX Spark. This platform transforms patient DNA into novel drug candidates in under 5 hours across three GPU-accelerated stages: Secondary Genomics, RAG-Grounded Target Identification, and AI-Driven Drug Discovery. Import this document into a Claude Code session as context for implementation.

License: Apache 2.0 | Author: Adam Jones | Date: February 2026

Table of Contents¶

Project Overview & Goals
DGX Spark Hardware Reference
Repository Layout
Docker Compose Services
Stage 1: Genomics Pipeline
Stage 2: RAG/Chat Pipeline
Milvus Vector Database Schema
Variant Annotation Pipeline
Knowledge Base — 201 Genes, 13 Therapeutic Areas
Anthropic Claude LLM Integration
Stage 3: Drug Discovery Pipeline
BioNeMo NIM Services
Drug-Likeness Scoring
Cryo-EM Structure Evidence
VCP/FTD Demo Walkthrough
Pydantic Data Models
Nextflow DSL2 Orchestration
Landing Page & Service Health
Monitoring Stack
Cross-Modal Integration
Configuration Reference
Deployment Roadmap
Testing Strategy
Implementation Sequence

1. Project Overview & Goals¶

What This Platform Does¶

The HCLS AI Factory is an end-to-end precision medicine platform that takes a patient's raw DNA sequencing data (FASTQ) and produces ranked novel drug candidates — all on a single NVIDIA DGX Spark desktop workstation. Three GPU-accelerated stages execute sequentially: variant calling, RAG-grounded target identification, and generative drug discovery.

Three-Stage Pipeline¶

Stage	Function	Duration	Key Output
1 — Genomics	BWA-MEM2 alignment + DeepVariant calling	120-240 min	VCF (~11.7M variants)
2 — RAG/Chat	Annotation → Embedding → LLM reasoning	Interactive	Target gene + evidence
3 — Drug Discovery	MolMIM generation → DiffDock docking → RDKit scoring	8-16 min	100 ranked drug candidates

End-to-End Flow¶

Patient DNA → Illumina Sequencer → FASTQ (~200 GB)
  → Parabricks fq2bam → BAM
  → DeepVariant → VCF (11.7M variants)
  → ClinVar + AlphaMissense + VEP annotation
  → Milvus vector indexing (3.5M embeddings)
  → Claude RAG reasoning → Target hypothesis (gene + evidence)
  → RCSB PDB structure retrieval
  → MolMIM molecule generation
  → DiffDock molecular docking
  → RDKit drug-likeness scoring
  → 100 ranked novel drug candidates + PDF report

Design Principles¶

GPU-first: Every compute-intensive step runs on the GB10 GPU
Clinically grounded: ClinVar, AlphaMissense, and VEP provide evidence-based annotation
Reproducible: Nextflow DSL2 orchestration with containerized processes
Open: Apache 2.0 license, open-source tools, public reference databases
Desktop-scale: Runs entirely on a $3,999 DGX Spark

2. DGX Spark Hardware Reference¶

Specifications¶

Parameter	Value
CPU	NVIDIA Grace (ARM64 / aarch64), 144 cores
GPU	NVIDIA GB10, 1 GPU
Memory	128 GB unified LPDDR5x (CPU + GPU shared pool)
System RAM	512 GB
Storage	NVMe, high-throughput I/O
Storage Access	GPUDirect Storage (zero-copy GPU access)
Price	$3,999
OS	Ubuntu-based (NVIDIA DGX OS)

Critical: ARM64 Architecture¶

ALL containers must be ARM64-compatible. The Grace CPU is aarch64, not x86_64. This affects: - Base Docker images (must use ARM64 variants) - Python wheel availability (most scientific packages have ARM64 wheels) - NVIDIA container images (use NGC ARM64 variants) - Any compiled C/C++ extensions (RDKit, BioPython)

Unified Memory Model¶

The 128 GB LPDDR5x is shared between CPU and GPU — there is no separate GPU VRAM. This means: - No explicit CPU→GPU data transfers needed for many operations - Memory pressure from CPU workloads reduces GPU-available memory - Monitor total system memory, not just "GPU memory" - Parabricks fq2bam peaks at ~40 GB, DeepVariant peaks at ~60 GB

Storage Requirements¶

Dataset	Size	Notes
GRCh38 reference	3.1 GB	Pre-indexed for BWA-MEM2
FASTQ input (30× WGS)	~200 GB	HG002 paired-end
BAM intermediate	~100 GB	Temporary, deleted after VCF
ClinVar database	~1.2 GB	4.1M clinical variants
AlphaMissense database	~4 GB	71M predictions
Milvus index	~2 GB	3.5M × 384-dim vectors
BioNeMo model cache	~10 GB	MolMIM + DiffDock weights
Total minimum	~320 GB	Plus OS and Docker layers

3. Repository Layout¶

hcls-ai-factory-public/
├── README.md                           # Project overview
├── LICENSE                             # Apache 2.0
├── docker-compose.yml                  # All services
├── start-services.sh                   # Service startup orchestration
├── .env.example                        # Environment variable template
│
├── hls-orchestrator/                   # Nextflow pipeline orchestration
│   ├── main.nf                         # DSL2 entry point
│   ├── nextflow.config                 # Profiles and parameters
│   ├── run_pipeline.py                 # Python CLI launcher
│   ├── modules/
│   │   ├── genomics.nf                 # Stage 1 processes
│   │   ├── rag_chat.nf                 # Stage 2 processes
│   │   ├── drug_discovery.nf           # Stage 3 processes
│   │   └── reporting.nf                # Report generation
│   └── tests/
│
├── genomics-pipeline/                  # Stage 1: Parabricks
│   ├── README.md                       # Genomics documentation (48 KB)
│   ├── Dockerfile
│   ├── src/
│   │   ├── run_parabricks.py           # fq2bam + DeepVariant launcher
│   │   ├── vcf_stats.py                # VCF quality statistics
│   │   └── web_portal.py               # Flask portal (:5000)
│   ├── config/
│   │   └── parabricks.yaml             # GPU resource allocation
│   └── tests/
│
├── rag-chat-pipeline/                  # Stage 2: RAG + Claude
│   ├── README.md                       # RAG documentation (51 KB)
│   ├── Dockerfile
│   ├── src/
│   │   ├── rag_engine.py               # Core RAG orchestration (23 KB)
│   │   ├── milvus_client.py            # Milvus vector DB client (13 KB)
│   │   ├── annotator.py                # ClinVar + AlphaMissense + VEP (23 KB)
│   │   ├── knowledge.py                # 201 genes, 13 areas (88 KB)
│   │   ├── streamlit_chat.py           # Chat UI (:8501)
│   │   └── api.py                      # REST API (:5001)
│   ├── config/
│   │   └── milvus.yaml                 # Vector DB configuration
│   └── tests/
│
├── drug-discovery-pipeline/            # Stage 3: BioNeMo + RDKit
│   ├── README.md                       # Drug discovery documentation (56 KB)
│   ├── Dockerfile
│   ├── src/
│   │   ├── pipeline.py                 # 10-stage orchestration (18 KB)
│   │   ├── nim_clients.py              # MolMIM + DiffDock clients (15 KB)
│   │   ├── molecule_generator.py       # SMILES generation (11 KB)
│   │   ├── cryoem_evidence.py          # Cryo-EM structure scoring (6 KB)
│   │   ├── models.py                   # Pydantic data models (8 KB)
│   │   ├── streamlit_discovery.py      # Discovery UI (:8505)
│   │   └── portal.py                   # Discovery portal (:8510)
│   ├── config/
│   │   └── discovery.yaml              # Pipeline parameters
│   └── tests/
│
├── landing-page/                       # HCLS AI Factory entry point
│   ├── Dockerfile
│   └── src/
│       └── landing.py                  # Flask landing page (:8080)
│
├── monitoring/                         # Observability stack
│   ├── prometheus.yml                  # Scrape configuration
│   └── grafana/
│       └── dashboards/
│           └── hcls-factory.json       # GPU + pipeline dashboard
│
└── docs/                               # Documentation
    ├── PRODUCT_DOCUMENTATION.txt       # Full product docs (122 KB)
    ├── ARCHITECTURE_MINDMAP.md         # Architecture reference
    └── PIPELINE_REPORT.md              # Pipeline analysis (29 KB)

4. Docker Compose Services¶

Port Allocation¶

Service	Port	Protocol	Stage
Landing Page	8080	HTTP (Flask)	Orchestration
Genomics Portal	5000	HTTP (Flask)	Stage 1
RAG REST API	5001	HTTP REST	Stage 2
Milvus Vector DB	19530	gRPC	Stage 2
Attu (Milvus UI)	8000	HTTP	Stage 2
Streamlit Chat	8501	HTTP	Stage 2
MolMIM NIM	8001	HTTP REST	Stage 3
DiffDock NIM	8002	HTTP REST	Stage 3
Discovery UI	8505	HTTP (Streamlit)	Stage 3
Discovery Portal	8510	HTTP	Stage 3
Grafana	3000	HTTP	Monitoring
Prometheus	9099	HTTP	Monitoring
Node Exporter	9100	HTTP	Monitoring
DCGM Exporter	9400	HTTP	Monitoring

Key Container Images¶

Service	Image	Notes
Parabricks	`nvcr.io/nvidia/clara/clara-parabricks:4.6.0-1`	GPU-accelerated genomics
Milvus	`milvusdb/milvus:v2.4-latest`	Vector database
MolMIM	`nvcr.io/nvidia/clara/bionemo-molmim:1.0`	Molecule generation NIM
DiffDock	`nvcr.io/nvidia/clara/diffdock:1.0`	Molecular docking NIM
Grafana	`grafana/grafana:10.2.2`	Dashboards
Prometheus	`prom/prometheus:v2.48.0`	Metrics TSDB

Service Startup Order¶

The start-services.sh script orchestrates startup in dependency order:

# 1. Infrastructure (Milvus, monitoring)
# 2. Stage 1 services (Parabricks, genomics portal)
# 3. Stage 2 services (RAG engine, Streamlit chat)
# 4. Stage 3 services (BioNeMo NIMs, discovery UI)
# 5. Landing page (health monitor for all 10 services)

Health Monitoring¶

The landing page at port 8080 monitors 10 services with periodic health checks:

Service	Health Endpoint	Check Interval
Parabricks	Port 5000 `/health`	30s
Milvus	Port 19530 gRPC ping	30s
RAG API	Port 5001 `/health`	30s
Chat UI	Port 8501 `/healthz`	30s
MolMIM NIM	Port 8001 `/v1/health/ready`	30s
DiffDock NIM	Port 8002 `/v1/health/ready`	30s
Discovery UI	Port 8505 `/healthz`	30s
Grafana	Port 3000 `/api/health`	30s
Prometheus	Port 9099 `/-/healthy`	30s
DCGM Exporter	Port 9400 `/metrics`	30s

5. Stage 1: Genomics Pipeline¶

Overview¶

Stage 1 takes raw FASTQ files from an Illumina sequencer and produces a Variant Call Format (VCF) file using NVIDIA Parabricks — a GPU-accelerated implementation of industry-standard bioinformatics tools.

Input Specifications¶

Parameter	Value
Sample	HG002 (GIAB reference standard)
Coverage	30× whole-genome sequencing (WGS)
Read Length	2×250 bp paired-end
File Size	~200 GB (FASTQ pair)
Reference Genome	GRCh38 (3.1 GB, pre-indexed)
Format	FASTQ (gzip-compressed)

Pipeline Steps¶

Step 1: BWA-MEM2 Alignment (`fq2bam`)¶

pbrun fq2bam \
  --ref /reference/GRCh38.fa \
  --in-fq /data/HG002_R1.fastq.gz /data/HG002_R2.fastq.gz \
  --out-bam /output/HG002.bam \
  --num-gpus 1

Metric	Value
Duration	20-45 minutes
GPU Utilization	70-90%
Peak Memory	~40 GB
Output	Sorted BAM + BAI index
Algorithm	BWA-MEM2 (GPU-accelerated)

Step 2: DeepVariant Variant Calling¶

pbrun deepvariant \
  --ref /reference/GRCh38.fa \
  --in-bam /output/HG002.bam \
  --out-variants /output/HG002.vcf.gz \
  --num-gpus 1

Metric	Value
Duration	10-35 minutes
GPU Utilization	80-95%
Peak Memory	~60 GB
Output	VCF (gzip-compressed + tabix index)
Algorithm	Google DeepVariant (CNN-based, >99% accuracy)

Output: VCF Statistics¶

Metric	Count
Total Variants	~11.7M
High-Quality (QUAL>30)	~3.5M
SNPs	~4.2M
Indels	~1.0M
Coding Region Variants	~35,000
Multi-allelic Sites	~150,000

Parabricks Container¶

Image: nvcr.io/nvidia/clara/clara-parabricks:4.6.0-1
GPU: Required (CUDA)
Volumes: /reference, /data, /output
Port: 5000 (Flask web portal for run status)

Genomics Portal (Port 5000)¶

The Flask-based portal provides: - Real-time pipeline progress monitoring - BAM quality statistics (mapping rate, duplication, coverage) - VCF summary statistics and variant type distributions - Run history and configuration logs

6. Stage 2: RAG/Chat Pipeline¶

Overview¶

Stage 2 annotates the VCF variants with clinical and functional databases, indexes them in a Milvus vector database, and uses Anthropic Claude with RAG to identify druggable gene targets supported by evidence.

Architecture¶

VCF (11.7M variants)
  → Quality filter (QUAL>30) → 3.5M variants
  → ClinVar annotation → clinical significance
  → AlphaMissense annotation → pathogenicity prediction
  → VEP annotation → functional consequences
  → BGE-small-en-v1.5 embedding → 384-dim vectors
  → Milvus IVF_FLAT indexing → 3.5M searchable embeddings
  → Claude RAG query → target hypothesis with evidence chain

Annotation Funnel¶

Stage	Variant Count	Filter
Raw VCF	~11.7M	—
Quality filter	~3.5M	QUAL > 30
ClinVar match	~35,616	Clinical significance annotated
AlphaMissense match	~6,831	AI pathogenicity predicted
Coding + pathogenic	~2,400	Actionable subset

Embedding Model¶

Parameter	Value
Model	BGE-small-en-v1.5
Dimensions	384
Input	Text summary of annotated variant
Index Type	IVF_FLAT
Index Params	nlist=1024
Search Params	nprobe=16
Distance Metric	COSINE
Total Embeddings	~3.5M

Query Flow¶

User asks a natural language question in the Streamlit chat
Query is expanded using 10 therapeutic area keyword maps
BGE-small-en-v1.5 embeds the expanded query
Milvus performs approximate nearest-neighbor search (top_k=20)
Retrieved variant contexts are assembled into a RAG prompt
Claude processes the prompt with knowledge base grounding
Response includes gene target, evidence chain, and confidence assessment

7. Milvus Vector Database Schema¶

Collection: `genomic_evidence`¶

Field	Type	Description
`id`	INT64 (PK, auto)	Primary key
`embedding`	FLOAT_VECTOR(384)	BGE-small-en-v1.5 embedding
`chrom`	VARCHAR(10)	Chromosome (chr1-chr22, chrX, chrY)
`pos`	INT64	Genomic position
`ref`	VARCHAR(1000)	Reference allele
`alt`	VARCHAR(1000)	Alternate allele
`qual`	FLOAT	Variant quality score
`gene`	VARCHAR(100)	Gene symbol (e.g., VCP, EGFR)
`consequence`	VARCHAR(200)	Functional consequence (e.g., missense_variant)
`impact`	VARCHAR(20)	Impact level (HIGH, MODERATE, LOW, MODIFIER)
`genotype`	VARCHAR(10)	Sample genotype (0/1, 1/1, etc.)
`text_summary`	VARCHAR(2000)	Human-readable variant description
`clinical_significance`	VARCHAR(200)	ClinVar classification
`rsid`	VARCHAR(20)	dbSNP identifier (e.g., rs188935092)
`disease_associations`	VARCHAR(2000)	Associated diseases/conditions
`am_pathogenicity`	FLOAT	AlphaMissense pathogenicity score (0-1)
`am_class`	VARCHAR(20)	AlphaMissense class (pathogenic/ambiguous/benign)

Total: 17 fields

Index Configuration¶

index_params = {
    "index_type": "IVF_FLAT",
    "metric_type": "COSINE",
    "params": {"nlist": 1024}
}

search_params = {
    "metric_type": "COSINE",
    "params": {"nprobe": 16}
}

Milvus Infrastructure¶

Component	Port	Purpose
Milvus standalone	19530	gRPC vector operations
Attu UI	8000	Web-based Milvus management
etcd	2379	Metadata storage
MinIO	9000	Object storage for indexes

8. Variant Annotation Pipeline¶

ClinVar Integration¶

Parameter	Value
Database	ClinVar (NCBI)
Total Variants	4.1M clinical variants
Match Rate	~35,616 / 3.5M variants (1.0%)
Classifications	Pathogenic, Likely pathogenic, VUS, Likely benign, Benign
Update Frequency	Monthly releases
Key Fields	Clinical significance, disease associations, review status

AlphaMissense Integration¶

Parameter	Value
Database	AlphaMissense (DeepMind)
Total Predictions	71,697,560 missense variant predictions
Match Rate	~6,831 / 35,616 ClinVar variants (19.2%)
Model	AlphaFold-derived protein structure features
Output	Pathogenicity score (0.0-1.0)

AlphaMissense Thresholds:

Class	Score Range	Interpretation
Pathogenic	> 0.564	Likely disease-causing
Ambiguous	0.34 - 0.564	Uncertain significance
Benign	< 0.34	Likely neutral

Ensembl VEP Integration¶

Parameter	Value
Tool	Ensembl Variant Effect Predictor (VEP)
Purpose	Functional consequence annotation
Output	Gene, transcript, consequence type, impact level
Impact Levels	HIGH, MODERATE, LOW, MODIFIER
Key Consequences	missense_variant, stop_gained, frameshift_variant, splice_donor_variant

Annotation Pipeline Code Pattern¶

# From annotator.py — three-database annotation pipeline
def annotate_variants(vcf_path: str) -> List[AnnotatedVariant]:
    """
    Pipeline: VCF → ClinVar → AlphaMissense → VEP → Annotated variants
    """
    variants = parse_vcf(vcf_path, min_qual=30)        # ~3.5M pass filter
    variants = annotate_clinvar(variants)                # Clinical significance
    variants = annotate_alphamissense(variants)          # AI pathogenicity
    variants = annotate_vep(variants)                    # Functional consequences
    return variants

9. Knowledge Base — 201 Genes, 13 Therapeutic Areas¶

Gene Distribution¶

Therapeutic Area	Gene Count	Example Genes
Neurology	36	VCP, APP, PSEN1, MAPT, SOD1, FUS, C9orf72
Oncology	27	EGFR, BRAF, KRAS, TP53, BRCA1, BRCA2, PIK3CA
Metabolic	22	GCK, PPARG, SLC2A2, ABCA1, PCSK9
Infectious Disease	21	ACE2, CCR5, IFITM3, TLR4, TMPRSS2
Respiratory	13	CFTR, SERPINA1, MUC5B, TERT
Rare Disease	12	VCP, HTT, SMN1, DMD, CFTR
Hematology	12	HBB, HBA1, F5, JAK2, CALR
GI/Hepatology	12	HFE, ATP7B, NOD2, SERPINA1
Pharmacogenomics	11	CYP2D6, CYP2C19, CYP3A4, DPYD, TPMT
Ophthalmology	11	RHO, RPE65, RS1, ABCA4
Cardiovascular	10	LDLR, PCSK9, SCN5A, MYBPC3, KCNQ1
Immunology	9	HLA-B, TNF, IL6, JAK1, CTLA4
Dermatology	9	FLG, MC1R, TYR, KRT14
Total	201	171 druggable (85% druggability)

Knowledge Base Structure¶

Each gene entry in knowledge.py (88 KB) contains:

{
    "gene": "VCP",
    "uniprot": "P55072",
    "therapeutic_area": "Neurology",
    "diseases": ["Frontotemporal Dementia", "ALS", "IBMPFD"],
    "druggability": "High",
    "drug_targets": ["D2 ATPase domain", "N-D1 interface"],
    "known_inhibitors": ["CB-5083", "NMS-873"],
    "variant_hotspots": ["R155H", "R191Q", "A232E"],
    "pathway": "Ubiquitin-proteasome system",
    "mechanism": "AAA+ ATPase, protein homeostasis",
}

Query Expansion Maps¶

10 therapeutic area query expansion maps enrich user queries with domain-specific terminology:

QUERY_EXPANSION = {
    "oncology": ["tumor", "cancer", "neoplasm", "carcinoma", "mutation driver",
                  "somatic", "germline", "tumor suppressor", "oncogene"],
    "neurology": ["neurodegeneration", "dementia", "ALS", "Parkinson",
                   "Alzheimer", "frontotemporal", "motor neuron"],
    # ... 8 more therapeutic areas
}

10. Anthropic Claude LLM Integration¶

Configuration¶

Parameter	Value
Model	`claude-sonnet-4-20250514`
Temperature	0.3
Max Tokens	4096
API	Anthropic Messages API
Role	RAG-grounded clinical reasoning

RAG Prompt Structure¶

system_prompt = """You are a clinical genomics specialist analyzing patient
variant data. Ground all responses in the retrieved variant evidence and
knowledge base. Cite specific variants, genes, and clinical classifications.
When recommending drug targets, explain the evidence chain from variant
to disease mechanism to druggability assessment."""

user_prompt = f"""
## Retrieved Variant Evidence (top {top_k} matches)
{formatted_variants}

## Knowledge Base Context
{knowledge_context}

## User Question
{user_question}
"""

Response Format¶

Claude generates structured target hypotheses:

{
    "target_gene": "VCP",
    "confidence": "high",
    "evidence_chain": [
        "rs188935092 (chr9:35065263 G>A) — ClinVar: Pathogenic",
        "AlphaMissense: 0.87 (pathogenic, >0.564 threshold)",
        "VEP: missense_variant, HIGH impact",
        "Known drug target: CB-5083 (Phase I VCP inhibitor)",
        "Druggability: 0.92 (D2 ATPase domain, ~450Å³ pocket)"
    ],
    "therapeutic_area": "Neurology",
    "diseases": ["Frontotemporal Dementia", "ALS", "IBMPFD"],
    "recommended_action": "Proceed to drug discovery with VCP as primary target"
}

11. Stage 3: Drug Discovery Pipeline¶

Overview¶

Stage 3 takes a target gene hypothesis from Stage 2 and produces 100 ranked novel drug candidates using BioNeMo generative chemistry, molecular docking, and drug-likeness scoring.

10-Stage Pipeline¶

Stage	Process	Description
1	Initialize	Load target hypothesis, validate inputs
2	Normalize Target	Map gene → UniProt ID → PDB structures
3	Structure Discovery	Query RCSB PDB for Cryo-EM/X-ray structures
4	Structure Preparation	Score and rank structures, select best binding site
5	Molecule Generation	MolMIM generates novel SMILES from seed compound
6	Chemistry QC	RDKit validates chemical feasibility
7	Conformer Generation	RDKit 3D conformer embedding (ETKDG)
8	Molecular Docking	DiffDock predicts binding poses and affinities
9	Composite Ranking	Weighted scoring: 30% gen + 40% dock + 30% QED
10	Reporting	PDF report generation (ReportLab)

Pipeline Configuration¶

# From pipeline.py
PIPELINE_CONFIG = {
    "num_candidates": 100,
    "molmim_endpoint": "http://localhost:8001/v1/generate",
    "diffdock_endpoint": "http://localhost:8002/v1/dock",
    "min_qed": 0.3,
    "min_dock_score": -6.0,         # kcal/mol
    "scoring_weights": {
        "generation": 0.30,
        "docking": 0.40,
        "qed": 0.30
    }
}

UniProt Mappings¶

Gene	UniProt ID	Function
VCP	P55072	AAA+ ATPase, protein homeostasis
EGFR	P00533	Receptor tyrosine kinase
BRAF	P15056	Serine/threonine kinase
KRAS	P01116	GTPase signaling

12. BioNeMo NIM Services¶

MolMIM (Port 8001) — Molecule Generation¶

Parameter	Value
Endpoint	`POST http://localhost:8001/v1/generate`
Model	MolMIM (Molecular Masked Inverse Model)
Input	Seed SMILES string
Output	Novel SMILES candidates
Method	Masked language model on molecular tokens
Container	`nvcr.io/nvidia/clara/bionemo-molmim:1.0`

Request Format:

{
    "smiles": "CC(=O)Nc1ccc(O)cc1",
    "num_molecules": 100,
    "temperature": 0.7,
    "top_k": 50
}

Response Format:

{
    "molecules": [
        {"smiles": "CC(=O)Nc1ccc(O)c(F)c1", "score": 0.85},
        {"smiles": "CC(=O)Nc1ccc(O)c(Cl)c1", "score": 0.82}
    ]
}

DiffDock (Port 8002) — Molecular Docking¶

Parameter	Value
Endpoint	`POST http://localhost:8002/v1/dock`
Model	DiffDock (diffusion-based docking)
Input	Ligand SMILES + protein PDB structure
Output	Binding pose + affinity score (kcal/mol)
Method	Score-based generative diffusion model
Container	`nvcr.io/nvidia/clara/diffdock:1.0`

Request Format:

{
    "ligand_smiles": "CC(=O)Nc1ccc(O)c(F)c1",
    "protein_pdb": "<PDB file content or path>",
    "num_poses": 5
}

Response Format:

{
    "poses": [
        {"score": -8.7, "confidence": 0.92, "pose_pdb": "..."},
        {"score": -7.3, "confidence": 0.84, "pose_pdb": "..."}
    ]
}

Docking Score Interpretation¶

Score (kcal/mol)	Interpretation
-12 to -8	Excellent binding affinity
-8 to -6	Good binding affinity
-6 to -4	Moderate binding affinity
> -4	Weak binding affinity

13. Drug-Likeness Scoring¶

Lipinski's Rule of Five¶

Rule	Threshold	Description
Molecular Weight	≤ 500 Da	Oral absorption limit
LogP	≤ 5	Lipophilicity
H-Bond Donors	≤ 5	NH + OH groups
H-Bond Acceptors	≤ 10	N + O atoms

QED (Quantitative Estimate of Drug-likeness)¶

Range	Interpretation
> 0.67	Drug-like (favorable properties)
0.49 - 0.67	Moderate drug-likeness
< 0.49	Less drug-like

TPSA (Topological Polar Surface Area)¶

Range (Å²)	Interpretation
< 140	Good oral bioavailability
60-90	Optimal range
> 140	Poor oral absorption

Composite Scoring Formula¶

def compute_composite_score(gen_score, dock_score, qed_score):
    """
    Weighted composite: 30% generation + 40% docking + 30% QED

    Docking normalization: scale raw kcal/mol to 0-1 range
    dock_normalized = max(0, min(1, (10 + dock_score) / 20))

    Example: dock_score = -8.5 → (10 + (-8.5)) / 20 = 0.075 → normalized
    """
    dock_normalized = max(0.0, min(1.0, (10.0 + dock_score) / 20.0))

    composite = (
        0.30 * gen_score +
        0.40 * dock_normalized +
        0.30 * qed_score
    )
    return composite

RDKit Property Calculation¶

from rdkit import Chem
from rdkit.Chem import Descriptors, QED

def calculate_properties(smiles: str) -> dict:
    mol = Chem.MolFromSmiles(smiles)
    return {
        "molecular_weight": Descriptors.MolWt(mol),
        "logp": Descriptors.MolLogP(mol),
        "hbd": Descriptors.NumHDonors(mol),
        "hba": Descriptors.NumHAcceptors(mol),
        "tpsa": Descriptors.TPSA(mol),
        "qed": QED.qed(mol),
        "rotatable_bonds": Descriptors.NumRotatableBonds(mol),
        "lipinski_pass": all([
            Descriptors.MolWt(mol) <= 500,
            Descriptors.MolLogP(mol) <= 5,
            Descriptors.NumHDonors(mol) <= 5,
            Descriptors.NumHAcceptors(mol) <= 10,
        ])
    }

14. Cryo-EM Structure Evidence¶

Structure Scoring Algorithm¶

The pipeline automatically retrieves and scores protein structures from RCSB PDB:

def score_structure(structure: StructureInfo) -> float:
    """
    Score a PDB structure for suitability in drug discovery.

    Factors:
    - Resolution: lower is better (max 5 Å cutoff)
    - Inhibitor-bound: +3 bonus (binding site already defined)
    - Druggable pockets: +0.5 per pocket
    - Cryo-EM method: +0.5 (modern technique bonus)
    """
    score += max(0, 5.0 - resolution)               # Resolution: 0-5 scale
    if has_inhibitor_bound:
        score += 3.0
    score += num_druggable_pockets * 0.5
    if 'Cryo-EM' in method:
        score += 0.5
    return score

VCP Structures (Demo)¶

PDB ID	Resolution	Method	Description	Score
8OOI	2.9 Å	Cryo-EM	WT VCP hexamer	High
9DIL	3.2 Å	Cryo-EM	Mutant VCP	High
7K56	2.5 Å	Cryo-EM	VCP complex	Highest
5FTK	2.3 Å	X-ray	VCP + CB-5083 inhibitor	Highest (inhibitor-bound)

VCP Binding Site¶

Parameter	Value
Domain	D2 ATPase domain
Mechanism	ATP-competitive inhibition
Pocket Volume	~450 Å³
Druggability Score	0.92
Key Residues	ALA464, GLY479, ASP320, GLY215

15. VCP/FTD Demo Walkthrough¶

Demo Target: Valosin-Containing Protein (VCP/p97)¶

Parameter	Value
Gene	VCP
Protein	p97 / Valosin-Containing Protein
UniProt	P55072
Function	AAA+ ATPase, ubiquitin-proteasome pathway
Diseases	Frontotemporal Dementia (FTD), ALS, IBMPFD
Variant	rs188935092 (chr9:35065263 G>A)
ClinVar	Pathogenic
AlphaMissense	0.87 (pathogenic, >0.564 threshold)
Seed Compound	CB-5083 (Phase I clinical VCP inhibitor)

Demo Flow¶

Stage 1 — Genomics (Demo Mode: ~20 min): 1. Load pre-processed HG002 FASTQ subset 2. Run Parabricks fq2bam alignment 3. Run DeepVariant variant calling 4. Output VCF with ~11.7M variants including rs188935092

Stage 2 — RAG/Chat (Interactive): 1. VCF annotated: ClinVar flags rs188935092 as pathogenic in VCP 2. AlphaMissense scores the missense variant at 0.87 (pathogenic) 3. 3.5M variants embedded and indexed in Milvus 4. User queries: "What are the most promising drug targets in this patient's genome?" 5. Claude identifies VCP with full evidence chain 6. Target hypothesis: VCP → FTD → druggable D2 ATPase domain

Stage 3 — Drug Discovery (~10 min): 1. VCP → UniProt P55072 → PDB structure retrieval 2. Cryo-EM structures scored: 8OOI, 9DIL, 7K56, 5FTK 3. 5FTK selected (inhibitor-bound, highest score) 4. CB-5083 seed SMILES → MolMIM generates 100 novel analogs 5. RDKit validates Lipinski, QED, TPSA 6. DiffDock docks each candidate against VCP D2 domain 7. Composite ranking: 30% generation + 40% docking + 30% QED 8. Top candidates: novel VCP inhibitors with improved drug-likeness 9. PDF report generated via ReportLab

Expected Demo Output¶

Pipeline: HCLS AI Factory — VCP/FTD Demo
Target: VCP (P55072) — Frontotemporal Dementia
Seed: CB-5083 (ATP-competitive VCP inhibitor)
Structure: 5FTK (2.3 Å, X-ray, inhibitor-bound)

Results:
- 100 novel VCP inhibitor candidates generated
- 87 pass Lipinski's Rule of Five
- 72 have QED > 0.67 (drug-like)
- Top 10 show docking scores -8.2 to -11.4 kcal/mol
- Composite scores range 0.68-0.89

16. Pydantic Data Models¶

Core Models (from `models.py`)¶

from pydantic import BaseModel, Field
from typing import List, Optional
from enum import Enum

class TargetHypothesis(BaseModel):
    """Output from Stage 2 — RAG-identified drug target"""
    gene: str                          # e.g., "VCP"
    uniprot_id: str                    # e.g., "P55072"
    confidence: str                    # high, medium, low
    evidence_chain: List[str]          # Supporting evidence items
    therapeutic_area: str              # e.g., "Neurology"
    diseases: List[str]               # Associated conditions
    druggability_score: float          # 0-1 scale

class StructureInfo(BaseModel):
    """PDB structure metadata"""
    pdb_id: str                        # e.g., "8OOI"
    resolution: float                  # Angstroms
    method: str                        # ELECTRON MICROSCOPY, X-RAY DIFFRACTION
    title: str
    has_inhibitor: bool
    num_pockets: int
    score: float                       # Computed suitability score

class StructureManifest(BaseModel):
    """Collection of scored PDB structures for a target"""
    target_gene: str
    uniprot_id: str
    structures: List[StructureInfo]
    best_structure: str                # PDB ID of highest-scored

class MoleculeProperties(BaseModel):
    """RDKit-computed molecular properties"""
    smiles: str
    molecular_weight: float
    logp: float
    hbd: int                           # H-bond donors
    hba: int                           # H-bond acceptors
    tpsa: float                        # Topological polar surface area
    qed: float                         # Quantitative drug-likeness
    rotatable_bonds: int
    lipinski_pass: bool

class GeneratedMolecule(BaseModel):
    """MolMIM output — a novel molecule candidate"""
    smiles: str
    generation_score: float            # MolMIM confidence
    properties: Optional[MoleculeProperties]

class DockingResult(BaseModel):
    """DiffDock output — binding prediction"""
    ligand_smiles: str
    dock_score: float                  # kcal/mol (negative = better)
    confidence: float                  # 0-1 model confidence
    pose_pdb: Optional[str]            # PDB-format binding pose

class RankedCandidate(BaseModel):
    """Final ranked drug candidate with composite score"""
    rank: int
    smiles: str
    generation_score: float
    dock_score: float
    qed: float
    composite_score: float             # 30% gen + 40% dock + 30% QED
    lipinski_pass: bool
    molecular_weight: float
    logp: float

class PipelineConfig(BaseModel):
    """Pipeline execution configuration"""
    mode: str                          # full, target, drug, demo, genomics_only
    num_candidates: int = 100
    min_qed: float = 0.3
    min_dock_score: float = -6.0
    molmim_url: str = "http://localhost:8001/v1/generate"
    diffdock_url: str = "http://localhost:8002/v1/dock"

class PipelineRun(BaseModel):
    """Complete pipeline execution record"""
    run_id: str
    mode: str
    target: Optional[TargetHypothesis]
    structures: Optional[StructureManifest]
    candidates: List[RankedCandidate]
    total_generated: int
    total_passed_qc: int
    total_docked: int
    duration_seconds: float
    status: str                        # running, completed, failed

17. Nextflow DSL2 Orchestration¶

Pipeline Modes¶

Mode	Stages	Description
`full`	1 → 2 → 3	Complete end-to-end pipeline
`target`	2 → 3	Skip genomics, use existing VCF
`drug`	3 only	Skip to drug discovery with known target
`demo`	1 → 2 → 3	Pre-configured VCP/FTD demonstration
`genomics_only`	1 only	Run only variant calling

Main Pipeline Entry (`main.nf`)¶

#!/usr/bin/env nextflow
nextflow.enable.dsl=2

include { GENOMICS_PIPELINE } from './modules/genomics'
include { RAG_CHAT_PIPELINE } from './modules/rag_chat'
include { DRUG_DISCOVERY_PIPELINE } from './modules/drug_discovery'
include { REPORTING } from './modules/reporting'

workflow {
    if (params.mode in ['full', 'demo', 'genomics_only']) {
        GENOMICS_PIPELINE(
            params.fastq_r1,
            params.fastq_r2,
            params.reference
        )
    }

    if (params.mode in ['full', 'demo', 'target']) {
        RAG_CHAT_PIPELINE(
            params.mode == 'target' ? params.vcf : GENOMICS_PIPELINE.out.vcf
        )
    }

    if (params.mode in ['full', 'demo', 'target', 'drug']) {
        DRUG_DISCOVERY_PIPELINE(
            params.mode == 'drug' ? params.target_gene : RAG_CHAT_PIPELINE.out.target
        )
    }

    REPORTING(
        DRUG_DISCOVERY_PIPELINE.out.candidates
    )
}

Nextflow Profiles¶

Profile	Description
`standard`	Default local execution
`docker`	Docker container execution
`singularity`	Singularity container execution
`dgx_spark`	DGX Spark optimized (GPU resources)
`slurm`	HPC cluster submission
`test`	Minimal test data

Pipeline Launcher (`run_pipeline.py`)¶

# Full pipeline
python run_pipeline.py --mode full \
  --fastq-r1 /data/HG002_R1.fastq.gz \
  --fastq-r2 /data/HG002_R2.fastq.gz \
  --reference /reference/GRCh38.fa

# Demo mode (pre-configured VCP/FTD)
python run_pipeline.py --mode demo

# Drug discovery only (known target)
python run_pipeline.py --mode drug --target-gene VCP --seed-smiles "CC(=O)..."

18. Landing Page & Service Health¶

Landing Page (Port 8080)¶

The Flask-based landing page serves as the entry point for the HCLS AI Factory:

URL: http://localhost:8080
Framework: Flask
Features:
10-service health status dashboard
Pipeline mode selector (full, target, drug, demo)
Quick-start links to all service UIs
Real-time service status with green/red indicators
Pipeline execution history

Service Health Check Implementation¶

SERVICES = [
    {"name": "Parabricks Portal", "url": "http://localhost:5000/health", "port": 5000},
    {"name": "Milvus Vector DB", "url": "http://localhost:19530", "port": 19530},
    {"name": "RAG API", "url": "http://localhost:5001/health", "port": 5001},
    {"name": "Streamlit Chat", "url": "http://localhost:8501/healthz", "port": 8501},
    {"name": "MolMIM NIM", "url": "http://localhost:8001/v1/health/ready", "port": 8001},
    {"name": "DiffDock NIM", "url": "http://localhost:8002/v1/health/ready", "port": 8002},
    {"name": "Discovery UI", "url": "http://localhost:8505/healthz", "port": 8505},
    {"name": "Grafana", "url": "http://localhost:3000/api/health", "port": 3000},
    {"name": "Prometheus", "url": "http://localhost:9099/-/healthy", "port": 9099},
    {"name": "DCGM Exporter", "url": "http://localhost:9400/metrics", "port": 9400},
]

19. Monitoring Stack¶

Grafana (Port 3000)¶

Parameter	Value
Image	`grafana/grafana:10.2.2`
Default User	admin / changeme
Dashboards	HCLS AI Factory (GPU, pipeline, services)
Data Source	Prometheus

Prometheus (Port 9099)¶

Parameter	Value
Image	`prom/prometheus:v2.48.0`
Internal Port	9090 → External 9099
Retention	30 days
Scrape Targets	Node Exporter, DCGM Exporter, service metrics

Node Exporter (Port 9100)¶

Metric Category	Examples
CPU	Usage %, load average, core temperatures
Memory	Used/free/cached, swap usage
Disk	I/O throughput, NVMe utilization, space
Network	Bandwidth, packet rates, error rates

DCGM Exporter (Port 9400)¶

Metric	Description
`DCGM_FI_DEV_GPU_UTIL`	GPU utilization percentage
`DCGM_FI_DEV_FB_USED`	GPU memory used (bytes)
`DCGM_FI_DEV_FB_FREE`	GPU memory free (bytes)
`DCGM_FI_DEV_GPU_TEMP`	GPU temperature (°C)
`DCGM_FI_DEV_POWER_USAGE`	GPU power draw (watts)
`DCGM_FI_DEV_SM_CLOCK`	SM clock frequency (MHz)

Key Dashboard Panels¶

GPU Utilization Timeline — fq2bam (70-90%) → DeepVariant (80-95%) → idle → MolMIM/DiffDock bursts
Pipeline Stage Progress — Stage 1/2/3 completion with timing
Memory Pressure — Unified memory usage across CPU + GPU workloads
Service Health Grid — Green/red status for all 10 services
Variant Processing Rate — Variants annotated per second
Drug Discovery Throughput — Molecules generated/docked per minute

HCLS AI Factory Ecosystem¶

The genomics-to-drug-discovery pipeline integrates with the broader HCLS AI Factory:

Imaging Intelligence Agent (CT/MRI/X-Ray)
    │
    ├── Lung-RADS 4B+ finding
    │       ↓
    │   FHIR ServiceRequest
    │       ↓
    ├── Trigger genomics analysis (Parabricks)
    │       ↓
    │   Tumor gene profiling
    │       ↓
    └── Drug candidates → Combined imaging + genomics report

Trigger	Source	Target	Action
Lung-RADS 4B+	Imaging Agent	Genomics Pipeline	Initiate tumor profiling
Pathogenic Variant	Genomics Pipeline	Drug Discovery	Generate targeted therapies
Drug Candidates	Drug Discovery	Imaging Agent	Combined clinical report

NVIDIA FLARE — Federated Learning¶

For multi-site deployments (Phase 3), NVIDIA FLARE enables federated model training: - Models train locally at each site - Only model updates (not patient data) are shared - Aggregation server combines updates - Privacy-preserving: raw genomic data never leaves the institution

21. Configuration Reference¶

Environment Variables¶

Variable	Default	Description
`ANTHROPIC_API_KEY`	(required)	Anthropic API key for Claude
`NGC_API_KEY`	(required)	NVIDIA NGC key for BioNeMo NIMs
`REFERENCE_GENOME`	`/reference/GRCh38.fa`	Path to GRCh38 reference
`MILVUS_HOST`	`localhost`	Milvus server hostname
`MILVUS_PORT`	`19530`	Milvus gRPC port
`MOLMIM_URL`	`http://localhost:8001`	MolMIM NIM endpoint
`DIFFDOCK_URL`	`http://localhost:8002`	DiffDock NIM endpoint
`CLAUDE_MODEL`	`claude-sonnet-4-20250514`	Claude model identifier
`CLAUDE_TEMPERATURE`	`0.3`	LLM temperature
`PIPELINE_MODE`	`full`	Pipeline execution mode
`NUM_CANDIDATES`	`100`	Number of drug candidates to generate
`MIN_QED`	`0.3`	Minimum QED threshold
`MIN_DOCK_SCORE`	`-6.0`	Minimum docking score (kcal/mol)
`GRAFANA_USER`	`admin`	Grafana admin username
`GRAFANA_PASSWORD`	`changeme`	Grafana admin password

AlphaMissense Thresholds¶

AM_PATHOGENIC_THRESHOLD = 0.564
AM_AMBIGUOUS_LOWER = 0.34
AM_AMBIGUOUS_UPPER = 0.564
AM_BENIGN_THRESHOLD = 0.34

Scoring Weights¶

SCORING_WEIGHTS = {
    "generation": 0.30,   # MolMIM generation confidence
    "docking": 0.40,      # DiffDock binding affinity
    "qed": 0.30           # RDKit drug-likeness
}

Drug-Likeness Thresholds¶

LIPINSKI = {
    "max_mw": 500,        # Molecular weight (Da)
    "max_logp": 5,        # Partition coefficient
    "max_hbd": 5,         # H-bond donors
    "max_hba": 10         # H-bond acceptors
}

QED_THRESHOLDS = {
    "drug_like": 0.67,    # QED > 0.67
    "moderate": 0.49,     # 0.49 < QED < 0.67
    "less_drug_like": 0   # QED < 0.49
}

DOCKING_THRESHOLDS = {
    "excellent": -8.0,    # kcal/mol
    "good": -6.0,
    "moderate": -4.0,
    "minimum": -6.0       # Pipeline cutoff
}

22. Deployment Roadmap¶

Phase 1: Proof Build¶

Parameter	Value
Hardware	NVIDIA DGX Spark ($3,999)
Orchestration	Docker Compose
Scale	Single patient, sequential processing
Timeline	Proof of concept
GPU	1× GB10
Memory	128 GB unified

Phase 2: Departmental¶

Parameter	Value
Hardware	1-2× DGX B200
Orchestration	Kubernetes
Scale	Multiple concurrent patients
GPU	8× B200 per node
Memory	1-2 TB HBM3e
Networking	InfiniBand

Phase 3: Enterprise / Multi-Site¶

Parameter	Value
Hardware	DGX SuperPOD
Orchestration	Kubernetes + NVIDIA FLARE
Scale	Thousands of concurrent patients
GPU	Hundreds of B200 GPUs
Networking	InfiniBand fabric
Privacy	Federated learning (data stays local)

Scaling Considerations¶

Bottleneck	Phase 1 Solution	Phase 2+ Solution
Genomics throughput	Sequential (1 sample)	Parallel Parabricks instances
Milvus query latency	Single-node Milvus	Milvus cluster with sharding
BioNeMo inference	Single NIM per model	Multiple NIM replicas
Storage I/O	NVMe direct	GPUDirect Storage + RAID

23. Testing Strategy¶

Unit Tests¶

Component	Test Focus
VCF Parser	Variant extraction, quality filtering
Annotator	ClinVar/AlphaMissense/VEP lookup accuracy
Milvus Client	Index creation, search recall
MolMIM Client	SMILES generation, request format
DiffDock Client	Docking request/response parsing
RDKit Scoring	Lipinski, QED, TPSA calculations
Composite Scorer	Weight application, normalization

Integration Tests¶

Test	Validates
VCF → Annotation → Milvus	End-to-end Stage 2 pipeline
Target → PDB → MolMIM → DiffDock	End-to-end Stage 3 pipeline
Health check endpoints	All 10 services responding
Nextflow modes	full, target, drug, demo execution

Demo Mode Validation¶

The demo pipeline mode uses pre-configured inputs to validate the complete pipeline: - Input: HG002 FASTQ subset (smaller dataset for faster execution) - Expected: VCP identified as target with rs188935092 evidence - Expected: 100 novel VCP inhibitor candidates ranked - Validation: Top candidates show improved QED vs CB-5083 seed

24. Implementation Sequence¶

Recommended Build Order¶

Infrastructure: Docker Compose, Milvus, monitoring stack
Stage 1 — Genomics: Parabricks container, fq2bam, DeepVariant, VCF output
Stage 2 — Annotation: ClinVar + AlphaMissense + VEP pipeline
Stage 2 — Vector DB: Milvus schema, BGE embedding, IVF_FLAT index
Stage 2 — RAG: Claude integration, knowledge base, query expansion
Stage 2 — Chat UI: Streamlit interface, REST API
Stage 3 — Structure: RCSB PDB retrieval, Cryo-EM scoring
Stage 3 — Generation: MolMIM NIM, molecule generation
Stage 3 — Docking: DiffDock NIM, binding prediction
Stage 3 — Scoring: RDKit properties, composite ranking
Stage 3 — Reporting: PDF generation, Discovery UI
Orchestration: Nextflow DSL2, pipeline modes, landing page
Testing: Unit tests, integration tests, demo mode validation
Monitoring: Grafana dashboards, alerting rules

Key Dependencies¶

GRCh38 reference → BWA-MEM2 index → fq2bam alignment
ClinVar + AlphaMissense databases → Annotation pipeline
Milvus running → Embedding indexing → RAG queries
BioNeMo NIMs running → Molecule generation + docking
All services healthy → Landing page green status

This Project Bible is the authoritative technical reference for the HCLS AI Factory. All other documentation assets (White Paper, Demo Guide, Intelligence Report, Learning Guides) derive their technical details from this source.

HCLS AI Factory — Project Bible¶

Table of Contents¶

1. Project Overview & Goals¶

What This Platform Does¶

Three-Stage Pipeline¶

End-to-End Flow¶

Design Principles¶

2. DGX Spark Hardware Reference¶

Specifications¶

Critical: ARM64 Architecture¶

Unified Memory Model¶

Storage Requirements¶

3. Repository Layout¶

4. Docker Compose Services¶

Port Allocation¶

Key Container Images¶

Service Startup Order¶

Health Monitoring¶

5. Stage 1: Genomics Pipeline¶

Overview¶

Input Specifications¶

Pipeline Steps¶

Step 1: BWA-MEM2 Alignment (fq2bam)¶

Step 2: DeepVariant Variant Calling¶

Output: VCF Statistics¶

Parabricks Container¶

Genomics Portal (Port 5000)¶

6. Stage 2: RAG/Chat Pipeline¶

Overview¶

Architecture¶

Annotation Funnel¶

Embedding Model¶

Query Flow¶

7. Milvus Vector Database Schema¶

Collection: genomic_evidence¶

Index Configuration¶

Milvus Infrastructure¶

8. Variant Annotation Pipeline¶

ClinVar Integration¶

AlphaMissense Integration¶

Ensembl VEP Integration¶

Annotation Pipeline Code Pattern¶

9. Knowledge Base — 201 Genes, 13 Therapeutic Areas¶

Gene Distribution¶

Knowledge Base Structure¶

Query Expansion Maps¶

10. Anthropic Claude LLM Integration¶

Configuration¶

RAG Prompt Structure¶

Response Format¶

11. Stage 3: Drug Discovery Pipeline¶

Overview¶

10-Stage Pipeline¶

Pipeline Configuration¶

UniProt Mappings¶

12. BioNeMo NIM Services¶

MolMIM (Port 8001) — Molecule Generation¶

DiffDock (Port 8002) — Molecular Docking¶

Docking Score Interpretation¶

13. Drug-Likeness Scoring¶

Lipinski's Rule of Five¶

QED (Quantitative Estimate of Drug-likeness)¶

TPSA (Topological Polar Surface Area)¶

Composite Scoring Formula¶

RDKit Property Calculation¶

14. Cryo-EM Structure Evidence¶

Structure Scoring Algorithm¶

VCP Structures (Demo)¶

VCP Binding Site¶

15. VCP/FTD Demo Walkthrough¶

Demo Target: Valosin-Containing Protein (VCP/p97)¶

Demo Flow¶

Expected Demo Output¶

16. Pydantic Data Models¶

Core Models (from models.py)¶

17. Nextflow DSL2 Orchestration¶

Pipeline Modes¶

Main Pipeline Entry (main.nf)¶

Nextflow Profiles¶

Pipeline Launcher (run_pipeline.py)¶

Step 1: BWA-MEM2 Alignment (`fq2bam`)¶

Collection: `genomic_evidence`¶

Core Models (from `models.py`)¶

Main Pipeline Entry (`main.nf`)¶

Pipeline Launcher (`run_pipeline.py`)¶