Week 5 HW: Protein Design II

Part 1: Generate Binders with PepMLM

I retrieved the human SOD1 sequence from UniProt (P00441) in FASTA format.

Original canonical sequence:

>sp|P00441|SODC_HUMAN Superoxide dismutase [Cu-Zn] OS=Homo sapiens OX=9606 GN=SOD1 PE=1 SV=2
MATKAVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTS
AGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVV
HEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ

I introduced the A4V mutation by changing Alanine (A) to Valine (V) at position 4 of the mature protein sequence (index 4, 0-based).

Mutant SOD1-A4V sequence:

MATKVVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTS
AGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVV
HEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ

The change is visible at positions 4-5: the original MATKA... becomes MATKV...

Using the PepMLM-650M Colab, I ran the model with the following parameters:

ParameterValue
Target sequenceSOD1-A4V (mutant)
Peptide length12
Top-K3
Number of binders4

I generated 4 peptides conditioned on the SOD1-A4V sequence, and added the known SOD1-binding peptide FLYRWLPSRRGG as a positive control for comparison.

Perplexity indicates PepMLM’s confidence that a peptide will bind the target — lower scores indicate higher confidence.

PepMLM perplexity scores output PepMLM perplexity scores output

Part 2: Evaluate Binders with AlphaFold3

Part 3: Evaluate Properties of Generated Peptides in the PeptiVerse

Part 4: Generate Optimized Peptides with moPPIt