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Docking-I_sc values do not correlate

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Docking-I_sc values do not correlate


I am new to Rosetta3 and have been trying to run some docking simulation of two ligands to a known protein PDB. I preapre the PDB as per the docking protocol (found at Meiler Lab tutorials). I prepare the ligands using SMILES converted by OpenBabel to structures. I ensure the structures reflect pH 7.4 and I also generate confomers using OpenBabel rather than BCL. The ligands are converted to .params. I run the rosetta_scripts.mpi.linuxgccrelease scripts @options.txt using the provided dock.xml. It appears the ligands are both docking correctly in the generated structures however the I_sc values provided in the file do not reflect the known Kd values for both the ligands (stronger binder shows smaller I_sc than weaker binder for best docked structure). If any insight could be provided why this may be happening that would be aprpeciated. I am just concerned I am using improper ligand formating which is causing these observed I_sc.


Post Situation: 
Wed, 2020-08-12 08:08

There are a few factors to consider...


  • Dissociation constant is different from binding energy. They correlate and some paper even plot kcat/KM vs. ∆∆G: But the former depends on alternative bindings etc. and a form of steered MD (molecular undocking) is needed in some cases to better hone in on the dissociation constant, especially for proteins with narrow entranceways. In this Stack Exchange Bioinfo Q&A for example I discuss a nasty protein, Cytochrome P450, whose enconter complex ∆∆G has no influence on the specificity/reactivity, which is fully dictated by how the ligand gets in. I once heard for a protein and its substrate being described as a "ship in a bottle".
  • Accuracy. The accuracy of any free energy scores is 1 kcal/mol or worse for any computational biochemistry method, even FEP by MD.
  • A priori ligand properties. The ligand itself without protein influences how it well it binds:
  • Partition coefficient. A variant of the above: the ∆∆G is the difference from unbound, which is in aqueous solvent. What if one has a much higher partition coefficient? How this influences Kd assays is causing weird buffer specific results —There is no simple way to calculate the ∆G in membrane of a ligand with Rosetta.


  • Alternate protonations of sidechains are not sampled, except histidine tautomerisation.
  • Implicit solvent. Rosetta uses implicit solvent. Solvent interactions may help with the binding. There is a solvent placing protocol called SPaDES/hydrate.
  • Stuck in a local minimum. Maybe the conformation of the ligand and sidechains and backbone endowning the lowest minimum was not sampled —how does the distribution of ∆∆G from the replicates look?
  • AtomTypes may not be ideal fit—nitrile is wrong with `` for example.
  • How were the Gasteiger-Marsili partial charges calculated? If mol2 file from OBabel, then from there.
  • Rosetta does not have a Drude oscillator for polarisable ligands. If the ligand is strongly polarisable or tautomerises, parameterising both may help.




Wed, 2020-08-12 08:49

Thank you for the help.

Wed, 2020-08-12 08:56