Week 5 HW: Protein Design. Part 2

Part A

Some background:

• Mutations in SOD1 cause familial Amyotrophic Lateral Sclerosis (ALS)
• ALS is a heterogeneous, severe neurodegenerative disorder, the hallmark of which is an adult-onset loss of upper and lower motor neurons.
• It leads to a progressive paresis and atrophy of skeletal muscles, resulting in quadriplegia and fatal respiratory failure.
• The mutation subtly destabilizes the N-terminus, perturbs folding energetics, and promotes toxic aggregation.

Task: Design short peptides that bind mutant SOD1 & then decide which ones are worth advancing toward therapy.

UniProt retrieved AA sequence:

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

AA with A4V mutation:

MATKVVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTS AGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVV HEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ

Using the colab book, 4 peptides (12 AA in length) were predicted:

Based on the results, the best candidate for the future drug therapy would be: WRYGVVVAAHKK with a score of 8.06, indicating that the model has high confidence in its binding potential relative to the benchmark.