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Currently I'm doing an MD simulation of a protein-ligand complex using GROMACS.

In the tutorial it mentioned the process of Restraining the Ligand.

Why do we do it? Is it absolutely necessary?

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    $\begingroup$ I think in that tutorial, he restrained both the protein and the ligand. Usually you would restrain the system of interest, and then allow the solvent to equilibrate around it. $\endgroup$
    – S R Maiti
    Dec 24, 2021 at 16:52

1 Answer 1

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The cause to use restrains is due to a previous knowledge (i.e. experimental) of system behavior/characteristics that you want to include/retain/reproduce in your simulations.

In the case of protein-ligand complex simulations, they encode specifically prior knowledge about the macromolecular system to be simulated and is built of several components. These include the following1,2:

(i) Stereochemical information (e.g. bond distances, angles) about the constituent blocks (e.g. amino acids, nucleic acids) of macromolecules and the covalent links between them.

(ii) The internal consistency of macromolecules (e.g. non-crystallographic symmetry, if present).

(iii) Additional structural knowledge (similarity to known structures, current interatomic distances or secondary-structure elements etc.).

Another use of restrains is when refining the structure of macromolecule–ligand complexes using X-Ray crystallographic1:

The process of generating a set of restraints, or ‘dictionary’, for a small molecule involves (i) taking a description of the molecule as an input, (ii) processing its description to derive atom energy types and connectivities, and finally (iii) using this information to generate an idealized set of coordinates to allow fitting of the ligand to electron density and a list of geometric restraints with associated weights to allow the fitted ligand to be refined.

This can be think as similar when you run a molecular docking inside the active site region only instead of running a blind docking. Here, the active site is the most important region of the enzyme as it directly catalyzes the chemical reaction3.

The effect of restrains in simulations should be studied comparing its effects in the system free energy and entropy4.

References:
(1) R.A. Steinera, and J.A. Tucker. Keep it together: restraints in crystallographic refinement of macromolecule–ligand complexes. Acta Crystallogr. D Struct. Biol. 73(Pt 2): 93–102 (2017). (DOI: 10.1107/S2059798316017964)
(2) A. Sali, T.L. Blundell. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779-815 (1993). (DOI: 10.1006/jmbi.1993.1626)
(3) https://en.wikipedia.org/wiki/Active_site
(4) G. Heinzelmann, PhD Thesis. Computational Studies of Glutamate Transporters and Receptors, 2014. (link)

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