I am interested in performing ensemble-averaged docking where the distance restraints should be averaged over multiple binding poses of a peptide to a target protein. I have tried to dock two identical peptides to the same protein simultaneously with interactions between the two peptides turned off. However, I am not able to generate any structures where the two peptides actually overlap on the target structure, which they should.
Questions
How can I define ensemble-averaged restraints? A published result mentions that it is done with 0.5 weighting of the distance to each copy using PRE restraints, however, I do not know how to specify this in the context of the tbl file for results obtained through regular NOEs (or for PREs for that matter).
Usually we specify ‘OR’ to enable alternative choices in the tbl file but can the AIR or unambiguous restraint be defined with ‘AND’ so that two different SegIDs with different residues can be linked to the same contact on the protein target simultaneously?
Is there a template PRE-restraints file that I can use to modify to get this ensemble-averaged restraint set up?
Does the web-based docking support the ensemble-averaged multibody docking?
Any help regarding this is much appreciated. I would encourage the Haddock team to describe the feature of ensemble-averaged docking a bit better as it is highly relevant for many protein-peptide interactions.
1. How can I define ensemble-averaged restraints? A published result mentions that it is done with 0.5 weighting of the distance to each copy using PRE restraints, however, I do not know how to specify this in the context of the tbl file for results obtained through regular NOEs (or for PREs for that matter).
Simply define the restraint such as it combine both peptides (or even more). E.g. assuming that they have segid B and C:
assign (segid A and name XX) (not segid A and name YY) ...
This will calculate both distances to the two peptides. But if the restraints are already satisfied by one peptide, the other peptide can remain away in space. To avoid this problem I would suggest to define in addition centre of mass restraints. But again if one peptide is enough to satisfy the restraints no reason to go to ensemble averaging…
2. Usually we specify ‘OR’ to enable alternative choices in the tbl file but can the AIR or unambiguous restraint be defined with ‘AND’ so that two different SegIDs with different residues can be linked to the same contact on the protein target simultaneously?
See example below. ‘AND’ would not work because there is no atom having both segIDs. You must thus use ‘OR’. Another way of writing the above restraints which would be specific for 2 peptides (B and C) would be:
assign (segid A and name XX) ((segid B or segid C) and name YY) ...
4. Does the web-based docking support the ensemble-averaged multibody docking?'
Yes. Check in particular the new 2.4 server. You can turn off interactions between chains. In the third step of the submission (Docking parameter tab) you will find a Molecular interaction matrix