TRAIRC Technologies - Physics-Informed Nipah Binder Design

STRATEGY: Glycan-aware de novo miniprotein design targeting NiV-G receptor binding domain.

APPROACH: We designed compact three-helix bundle scaffolds (~66 AA) optimized for:

1. High predicted binding affinity to NiV-G ephrin-binding interface
2. Avoidance of N-glycosylation sites (positions 159, 195, 261, 309, 378, 417)
3. Low aggregation propensity and high predicted solubility
4. Minimal cysteine content to avoid disulfide complications

KEY DIFFERENTIATORS:

• Glycan-aware design: NiV-G has 6 occupied N-glycan sites in HEK293 cells. We explicitly filtered designs with interface residues proximal to these sites.
• Physics-based scoring: Composite ranking using predicted pLDDT, interface metrics (H-bonds, dSASA, shape complementarity), and expression likelihood.
• High mutation load: All designs have 12+ mutations from starting scaffolds, ensuring novelty.

SCAFFOLD: Three-helix bundle architecture chosen for:

• Compact size (66 AA) within competition limits
• High thermal stability
• Proven success in de novo binder design

COMPUTATIONAL PIPELINE:

1. Scaffold generation using helical repeat principles
2. Interface-focused mutagenesis targeting NiV-G hotspots
3. Filtering for solubility, low Cys count, charged residue balance
4. Ranking by composite physics score

HYPOTHESIS: Compact, glycan-clear miniproteins will achieve high binding affinity while avoiding steric clashes with NiV-G surface glycans, leading to better experimental validation rates.

All code and methodology available upon request. TRAIRC Technologies LLC - November 2025