Docking a small, flexible ligand on a quite flexible protein

I am docking a lipid on a nonspecific lipase. There is a “lid” close to the binding site that might need to move away for the lipid to enter the binding site. My docking runs have only got the ligand close to the outside of the binding site, but not in it. I think I need to change some parameters in run.cns.

The only changes I have done to run.cns are:

  • delenph = false (line 554)
  • histidine patches for my protein (568, 1158)
  • number of structures to dock set to 1000 for it0 and 200 for it1 (4375)
  • initiosteps, cool1_steps both 0 (4471)
  • final explicit solvent refinement: firstwater = no (4541)
  • w_vdw = 1.0 (4580)
  • clust_meth = RMSD; clust_cutoff = 1.0 (4658)

My reasoning is: I should probably do more steps in it1 and less in it0, because in it0 the protein is not flexible, the ligand cannot get in, so those steps are useless. Is that right?

In the manual, under the explanation of it0, it says:

Note: The translational minimization can be turned off in run.cns by setting rigidmini to false (default is true ). This option can be useful for example for small flexible molecules to perform the docking during the simulated annealing stage allowing conformational changes to take place during the docking process. The number of steps in the first two stages of the simulated annealing should then be increased by at least a factor four to allow the molecules to approach each other.

So should I not change initiosteps and cool1_steps to 0, and instead set rigidmini to false?

But in the FAQ about small ligand docking it says:

Also we recommend to set the number of MD steps for the first two parts (rigid-body high temperature dynamic and slow cooling annealing) of the semi-flexible refinement to 0.

There is no explanation about why you should set the number of MD steps for the first two parts of it1 to zero. Could you maybe explain to me why this is?


If the pocket is fully closed it will be hard to get your lipid in…

What can help is decreasing the intermolecular interactions for it0 to 0.01.

In run.cns:

{* Scaling of intermolecular interactions for rigid body EM*}
{===>} inter_rigid=0.01;

As for the other questions:

  • for the MD steps set to 0 for the first two stages of it1, it has to do with the high temperature and the risk of ejection of the ligand

  • don’t turn off rigid mini

  • you could increase the number of steps for the last two stages of it1, but if the ligand it not yet in the pocket it is unlikely it will help…

Finally check our recent paper on shape-restrained ligand docking, could be an option

1 Like