[gmx-users] ASN instead of ASP in the binding site: how to find the novel complex conformation ?

[Anton Feenstra]

Luca Mollica wrote:

> Dear all,
> 
> I am simulating protein dimer both without and with the ligand in the 
> binding site. The structure that I got from PDB has the ligand (a 
> molecule of ASP) in the binding site, and my goal is to simulate the 
> dynamics of the protein without the ligand and with a novel but similar 
> ligand (a molecule of ASN) that was put in the same position of the old 
> ligand but randomly oriented (in order to avoid any bias). The 
> simulation of the dimer without ligand was fine, but I have encountered 
> a big trouble during the ligand-dimer complex simulation, realising that 
> after 600-700 ps there was a separation of the two monomer, a loss in 
> sec.strucure and an almost stepwise increase of the radius of gyration 
> (also, the complex starts to rotate around an axis with great speed).
> 
> Therefore, I have two questions:
> 
> 1. Could anyone provide me an explanation for a strange event like 
> rotation ?
[...]
> The simulations have been performed using pbc, cut off electrostatics, 
> GROMACS FF and with implicit solvent (these are preliminary simulations).

You'll probably have to impose orientational restraints, which I haven't
used myself but should be available and trivial to turn on (mdp option).
That will solve your rotation. This actually is not so surprizing, the
accumulation of (roundoff and other) errors leads to buildup of random
velocities. The rotational motion doesn't couple with anyting else, so
it won't be dampened in any way.

pbc seems irrelevant with implicit solvent (but won't hurt either).

> 2. I am also thinking to use another approach to the problem, keeping 
> protein atomic positions restrained except the ones in the binding site: 
>  what do you think about it? Should I keep all the positions restrained ?

It is an additional approximation you'll be making. It will depend on
the type of system you simulate, and which questions you are asking.
I personally wouldn't use restraints unless unavoidable.

> "To reach a house, you must first enter the gate. The gate is the 
> pathway leading to the house. After passing through the gate, you enter 
> the house and meet its master. Learning is the gate to reaching the Way. 
> After passing through the gate, you reach the Way. Learning is the gate, 
> not the house. Don't mistake the gate for the house. The house is 
> located farther inside, after the gate is passed. Because learning is 
> the gate for the house, don't think books you read are the Way. Books 
> are a gate for reaching the Way."
>  (The Sword and The Mind)

Nice one!


-- 
Groetjes,

Anton
  _____________ _______________________________________________________
|             |                                                       |
|  _   _  ___,| K. Anton Feenstra                                     |
| / \ / \'| | | Dept. of Pharmacochem. - Vrije Universiteit Amsterdam |
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| \_/ \_/ | | | Tel: +31 20 44 47608 - Fax: +31 20 44 47610           |
|             | Feenstra at few.vu.nl - www.few.vu.nl/~feenstra/         |
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