Week 5 HW：Protein Design Part-ii
Part A: SOD1 Binder Peptide Design
Part 1: Generate Binders with PepMLM
Generate four peptides of length 12 amino acids conditioned on the mutant SOD1 sequence.
Among the generated sequences, WRYPAAAAELKK (7.61) stands out the most. It has a lower perplexity than the other generated sequences, indicating that it may be more compatible with the pocket of the SOD1 A4V mutation site in terms of chemical environment and geometric conformation.
Part 2: Evaluate Binders with AlphaFold3
For each peptide, I submit the mutant SOD1 sequence followed by the peptide sequence as separate chains to model the protein-peptide complex. And I analysis these 4 peptide from different perspective inculding engagement of the β-barrel region,surface-bound, ipTM values ,peptide matches.
Part 3: Evaluate Properties of Generated Peptides in the PeptiVerse
- Therapeutic Properties and Structural Observations: Comparative Analysis
By comparing the predicted data from PeptiVerse with the structural observations of AlphaFold3, we can draw the following conclusions:
Conformity between Binding Force and ipTM: Generally, short peptides with higher ipTM scores exhibit more stable interfacial interactions. In your prediction list, WRYPAAAAELKK showed the lowest perplexity score (7.61), which typically indicates stronger binding potential.
Solubility & Hemolysis:
Solubility: All candidate peptides (Binder 0-3) were predicted as Soluble (probability 1.000), which is a very desirable signal in therapeutic development.
Hemolysis: Most designs performed well and were predicted as Non-hemolytic. WRYPAAAAELKK showed an extremely low probability of hemolysis (0.005), indicating very high safety. In comparison, WLYYVVAVAWKK has a slightly higher hemolysis prediction probability (0.172), and although it is still classified as non-hemolytic, its safety profile is slightly inferior to other candidates.
The best performer in terms of attribute balance: WRYPAAAAELKK achieves the optimal balance between binding confidence, complete solubility, and extremely low risk of hemolysis.
- Final Candidate Short Peptide Selection and Rationale
WRYPAAAAELKK
Rationale: This short peptide stood out in the PepMLM score, possessing the lowest Pseudo Perplexity (7.61), indicating the model’s strongest confidence in its binding to SOD1 (A4V). In therapeutic property prediction, it not only demonstrated perfect solubility prediction (1.000) but also exhibited excellent safety indicators, with an ultra-low hemolysis probability of 0.005, making it the most robust therapeutic candidate. Its acid-base balance (pI 9.38) and hydrophobicity index (GRAVY -0.72) also suggest good biochemical stability in the complex physiological environment within cells.