Covalent Docking (Asn-Glycan Glycosidic Bond)

HADDOCK
1

I have a glycoprotein-to-protein complex and I suspect the flexible end of the glycan to be involved in binding. I want to dock the flexible side of the N-glycan to the whole two chain complex, with a distance restraint on the glycosidic bond between the glycan and the protein. This is similar to this example: Modelling a covalent inhibitor of cathepsin proteins – Bonvin Lab. Where the custom residue CYC is used:

A problem when trying to “covalently dock” a small ligand is that the van der Waals interactions will typically prevent close proximity of the atoms involved in the covalent bond. To allow the distance restraint to be satisfied, we need to scale down the non-bonded interactions between the specific atoms involved in that covalent bond. For this purpose we created a special Cysteine residue (residue name: CYC), without hydrgogen atom on the sulfur and with significantly reduced VDW parameters for the sulfur atom (scaled down by a factor 10).

However, no such thing exists for a ASN glycosidic bond. When I specify a distance restraint between the NAG and ASN (1.42 angstroms), HADDOCK fills in their hydrogens and OH which are overlapping with each other where there should be a glycosidic bond, creating huge Van der Waals energy. Is there any way to make a custom ASN residue like CYC? Or is there any workaround for this kind of thing?

2

There is no simple solution to that problem as we don’t have a special ASN defined for covalent docking.

But what you can do it to give the resulting model(s) to the HADDOCK refinement server, modifying the PDB file to have a single chainID (i.e. both the protein and your glycans should have the same chainID). HADDOCK should recognise the glycosylted ASN and create then the covalent bond (provided the distance is within 2A). If that distance cutoff is too short we can try increasing it.