Week 5 HW: Protein Design Part II

Part A: SOD1 Binder Peptide Design (From Pranam)

List peptides

Peptide 1

Peptide 2

Peptide 3

Peptide 4

The ipTM values observed serve as confidence markers from the AlphaFold model, representing the predicted reliability and strength of the binding interaction. Peptide 2, generated by PepMLM, is the most promising design with an ipTM of 0.82, which nearly coincides with the 0.85 score of the Known Binder. While none of the generated peptides technically surpass the known binder in this dataset, Peptide 2 demonstrates high potential for reducing mutant activity and could be a viable candidate for experimental validation, similar to the plaque assays used to test design effectiveness in the sources.

Peptide two (AHSGAVALEHGP) is the most similar to the known binder among the generated sequences. It achieved the highest ipTM score of the designed peptides at 0.820, which is remarkably close to the 0.850 of the known binder. Furthermore, its Pseudo Perplexity was 12.849, significantly lower than that of the reference binder. This peptide was predicted to bind at a “shallow pocket” [user summary]. ipTM and Affinity Correlation A higher ipTM score generally correlated with a stronger predicted binding affinity, which is consistent with the expected interpretation of the AlphaFold-Multimer ipTM metric used to evaluate these interactions. This metric serves as an important confidence marker for the reliability of the predicted binding. Diverse Binding Locations The generated peptides showed various predicted binding locations, including a shallow pocket, surface-bound, near the N-terminus (relevant to the aggressive A4V mutation), and an interface with a loop region. The ability to target diverse sites is critical for achieving the specificity required to inhibit the toxic aggregations of mutant SOD1.

PART C: L-Protein Mutants