# Task: end-to-end computational study of KRAS G12C
You are working as a computational biologist/chemist. Do real computation, not
mock data. Every number you report must come from code you ran. If a step fails
or a tool can't be installed, say so and use the closest working alternative.
Don't fabricate outputs.
Save all outputs in an organized directory (one folder per step) using standard
domain file formats, so they can be opened directly in viewers.
1. **Sequence & evolution**
- Fetch human KRAS, HRAS, NRAS + 10–15 RAS orthologs across species (UniProt).
- MSA (MAFFT or Clustal Omega), per-residue conservation scores.
- Phylogenetic tree (FastTree or IQ-TREE).
- Outputs: .fasta, .aln, .sto, .nwk, conservation.csv
2. **Structure**
- Download PDB 6OIM (KRAS G12C + sotorasib) and a wild-type GDP-bound KRAS.
- Clean, add hydrogens, protonate at pH 7.4.
- Superpose mutant vs wild-type, per-residue RMSD, identify the switch-II pocket.
- Write conservation scores into the B-factor column.
- Outputs: .pdb, .cif, .pqr, rmsd_per_residue.csv
3. **Cheminformatics**
- ~30 molecules: sotorasib, adagrasib, other KRAS inhibitors from ChEMBL, + decoys.
- RDKit: 3D conformers, descriptors (MW, logP, TPSA, HBD/HBA, QED), Lipinski,
Morgan fingerprints, Tanimoto similarity matrix, scaffold clustering.
- Outputs: .sdf, .mol2, .smi, .xyz, descriptors.csv, similarity_matrix.csv
4. **Docking**
- Dock into the switch-II pocket (Vina or smina). Redock sotorasib first and
report RMSD to the crystal pose. If > 2 Å, diagnose before continuing.
- Outputs: complex + pose files (.pdbqt, .sdf, .pdb), scores.csv
5. **Molecular dynamics**
- Short OpenMM run (explicit solvent, 1–5 ns, whatever hardware allows) on apo
KRAS G12C and the sotorasib complex.
- RMSD, RMSF, radius of gyration, ligand contacts over time.
- Outputs: topology .pdb + .dcd/.xtc trajectory, analysis CSVs
6. **Quantum chemistry**
- xtb, or psi4/pyscf with a small basis, on sotorasib's acrylamide warhead fragment:
optimized geometry, HOMO/LUMO, ESP, partial charges. Comment on electrophilicity.
- Outputs: .xyz, .molden, HOMO/LUMO/ESP .cube files
7. **Electrostatics**
- APBS on the protein.
- Outputs: .dx potential map
8. **Extra formats**: fetch or generate one real, relevant example of each:
- cryo-EM map of a RAS complex (.mrc/.map from EMDB)
- KRAS variants (.vcf from ClinVar/gnomAD), gene annotation (.gff3), region (.bed)
- GenBank record for KRAS (.gb)
- small-molecule crystal structure (.cif from COD)
- RAS/MAPK pathway (.sbml)
- mass spectrum (.mzML) or IR/NMR spectrum (.jdx) of a relevant compound
9. **Report** (markdown): methods with tool versions and parameters, key findings
with numbers, sanity checks passed/failed, limitations (short MD, small basis,
docking scoring caveats), next steps with more compute. Include a manifest
listing every output file, its format, and what it contains.
