Haddock: S-C bond broken after docking

HADDOCK
1

Hi!

I am trying to dock an antibody-drug conjugate (ADC) to a protein. In the pdb file with the antibody-drug conjugate I have a modified cysteine (CYC) connected to my ligand with a 0.8 A bond.
In the complexes that I get after the docking, the ligand from my ADC has moved far away from the antibody and the bond is not there anymore.
Here is the link for my run HADDOCK results page

I tried connecting my ligand to a different cysteine before and the docking of the ADC with the protein worked well, however this time my ADC had its ligand in the terminal cysteine, so I believe it is not staying connected due to the higher repulsion of the terminal cysteine.

Is there any way to solve this?
Thank you in advance.

2

Dear Joana

A few points:

  1. The covalent bond won’t be maintained. You should add some distance restraints to keep it.

  2. Your ligand seems very remote from the binding site, i.e. it does not matter :slight_smile: You can always put it back by superimposition

  3. You should define the antibody+ligand PDB file as “protein-ligand” when submitting it. In that way a few distance restraints should be automatically defined (but not the bond to CYC which you need to provide as a separate unambiguous file.

3

Dear Dr. Bonvin,

Thank you for the answer.
I tried using a distance restraint between the carbon and the sulphur, however it is not working.
I wrote:
assi (resid 215 and name C17 and segid A) (resid 215 and name SG and segid A) 1.7 1.7 0
I wanted the bond to stay with 1.7 A, however it still moved away.

4

Your CYC is residue 214… and not 215 based on what I see in a cluster PDB file

5

Sorry, my mistake. It worked now. Thank you.