# How to initiate protein-ligand docking with MD simulation tools

I have two PDB files (each corresponding to a ligand and a receptor). Each downloaded separately from PDB.

I'd like to perform ligand to protein docking process with MD with GROMACS or Amber.

Using those two files directly, does GROMACS/Amber automatically perform the docking for us? Or should we give the pre-docked PDB files? These pre-docked PDB files may come from rigid-body docking tools like ClusPro or flexible docking like FlexPepDock .

You can do it either way.

1. You need to give predocked files to GROMACS/Amber for running protein-ligand complex molecular simulations. Also have a look at HADDOCK web server for predocking.
2. Place the receptor outside the interaction range of your protein (randomly) and run an MD simulation, to find the binding regions. But you need to do multiple MD runs to make sure that the binding region observed is not an local minima (event).

And why outside the interaction range of the protein, This is to ensure that you results are not biased on the position of the ligand.

https://pubs.acs.org/doi/full/10.1021/cn300091a

• thanks so much. For no.2 you essentially meant that MD tools can and do perform docking am I right (i.e w/o predock)? And which way is the common practice? no 1 or 2? Oct 30, 2021 at 8:43
• The way MD finds a binding site is different from the actual docking servers do. Docking servers will do rigid docking. If you have good computational power, go for Number 2. And I highly recommend reading the work from Justin Lemkul where he explains the disadvantages of docking over MD (link attached in the answer) Oct 30, 2021 at 8:52
• thank again. How about docking with flexible dock is it the same with MD? Oct 30, 2021 at 9:00
• I am not sure about flexible docking(maybe someone can answer that). But I know one limitation which I observed. the number of flexible residues in docking is limited, so your results are dependent on the choice of flexible residues. Lets say, amyloid beta has 40 residues, and 9 chains (360 residues), As far as I know, autodock doesn't allow all 360 residues to be flexible. And docking may not reflect reality since protein adopts so many confirmations, docking to one (or even more) sites would be insufficient. Oct 30, 2021 at 9:04

Docking and Molecular dynamics are two very different process.

In docking, you will need the ligand (normally in a separate file), the protein (can be in a separate file too), and the information about the site where you want to dock the ligand. This information can be some residues or simple a (x,y,z) coordinate. Then the docking program will generate a library of initial ligand conformations, put in the site you specified and then score the interaction ligand/protein using a score function.
The docking software can do rigid/rigid docking (protein rigid/ligand rigid), rigid/flexible (protein rigid/ligand flexible) or flexible/flexible (protein flexible/ligand flexible). The last one is not always fully available.
This is a very fast technique where you can do virtual throughput screening with thousand of ligands even on a personal computer/notebook.

Molecular dynamics (MD) will need a protein/ligand complex with the ligand already in the site where you want to study the interactions. For this step you can use a complex resulting from a docking simulation or just a complex that you create in a molecular drawing software (you can load both molecules and them move the ligand until it is in the regions you want). The MD software then will solve the Newton's equation of movement where the position, velocity, acceleration and force on each atom is calculated.
In this case, both protein and ligand will be treated as flexible. MD is a very time and computational resource demanding task. The best way to perform MD is using a GPU.

• Thank you. Is MD the same with flexible docking (e.g. CABS-Dock or FlexPepDock)? Oct 30, 2021 at 14:01
• No. MD flexibility (both ligand and protein) evolve in time as the atoms interact each other. In docking, the flexibility is generated by the docking program, so, it is a "limited" flexibility (not as flexible as MD).
– Camps
Oct 30, 2021 at 19:27