Clashes with small molecule ligand

HADDOCK
1

Hi! I have been using HADDOCK locally to dock a small molecule binding to a protein using NOE distance restraints and CSPs. Everything appears to have worked but my docking solutions have clashes. The docking solutions produced show a somewhat buried binding site and a significant conformational change needs to occur. I wondered if you would be able to help me with how I can set up the docking to not have these clashes? The parameters I used for the docking are below:

{* Scaling of intermolecular interactions for rigid body EM*}
{===>} inter_rigid=1.0;

{* Scaling of intermolecular interactions for semi-flexible SA*}
{+ table: rows=3 "Rigid body dynamic " “SA with flexible side-chains (cool2)” “SA with flexible backbone and side-chains (cool3)” cols=2 “Init value” “Final value” +}
{===>} init_rigid=0.001;
{===>} fin_rigid=0.001;
{===>} init_cool2=0.001;
{===>} fin_cool2=1.0;
{===>} init_cool3=0.05;
{===>} fin_cool3=1.0;

Scoring:
{===>} w_vdw_0=0.01;
{===>} w_vdw_1=1.0;
{===>} w_vdw_2=1.0;

{===>} w_elec_0=1.0;
{===>} w_elec_1=1.0;
{===>} w_elec_2=0.2;

{===>} w_dist_0=0.01;
{===>} w_dist_1=0.1;
{===>} w_dist_2=0.1;

Thanks very much!

2

How do you measure those clashes?

This is rather strange since HADDOCK usually has very little clashes in the refined models.

Did you modify the scaling parameters you were showing in your original message?

I would only touch inter_rigid to allow to access buried, sites, e.g. putting it to 0.01

And setting then w_vdw_0=0;

And leave all other parameters to their default.

3

Thanks for getting back to me. I did try modifying inter_rigid and the scoring but I may not have had the parameters you suggested at the same time so will try that. There are pretty bad clashes with my protein backbone in the docked structures i.e backbone amides pointing towards each other within 2A. I was mainly looking at it1 structures not the water refined ones but it is the same in those. I wondered whether increasing the MD steps might be something to try?

4

Bad clashes in your protein might well be present before docking…
It would be strange if they were introduce by the docking.