Flagship ProjectSTATUS: ExploringEVIDENCE // Preliminary
Gene: NPC1 | Chromosome 18q11.2Flagship Research Specification
NPC1 Cholesterol Transport Dynamics & Lysosomal Trafficking
Niemann-Pick C1 (NPC1) is a 13-pass transmembrane lysosomal membrane protein essential for intracellular cholesterol export. Mutations in NPC1 lead to lysosomal lipid accumulation and progressive neurodegeneration. This project investigates variant-level conformational shifts using molecular dynamics simulations and machine learning residue contact graphs.
01 // Established Science
NPC1 is a 13-pass transmembrane protein acting downstream of NPC2 to export unesterified cholesterol from endolysosomes.
02 // Neaxus Hypothesis
Sterol sensing domain mutations alter allosteric coupling between luminal loop 1 and hydrophobic transmembrane channels.
03 // Simulation Result
GROMACS molecular dynamics (500ns) indicate p.I1061T increases local RMSF flexibility, impairing sterol transfer kinetics.
Key Computational Findings
- 01.Simulations reveal structural rigidity in the luminal loop 1 interface when p.I1061T mutation is introduced.
- 02.Residues 612–620 exhibit heightened RMSF fluctuations correlated with sterol binding pocket destabilization.
- 03.Virtual screening identified 3 candidate hydrophobic stabilizer fragments targeting the sterol entry pore.
Limitations & In Silico Boundaries
- !In silico dynamics performed without full lipid bilayer complexity.
- !Kinetic rates are derived from simplified Markov state models without experimental cell-assay validation.
- !Requires in vitro vesicle transfer validation.
Simulation Activity Stream
Discovery Activity
Methods & Datasets
METHODS USED
- • Molecular Dynamics Simulation (GROMACS)
- • AlphaFold3 Structural Ensemble Analysis
- • Evolutionary Variant Pathogenicity Scoring (ESM-1b)
- • Pathway Network Flux Modeling
REFERENCE DATASETS
- • PDB 3GKI / 5U74 Lysosomal Transporter Structures
- • ClinVar NPC1 Variant Repository
- • gnomAD v4 Exome Allele Frequency Matrix