AMBER Archive (2007)

Subject: AMBER: Ligand-Protein Distance Restraints during MD Simulation

From: Akshay Patny (akshay17_at_olemiss.edu)
Date: Fri Jan 26 2007 - 18:06:26 CST

Dear Amberites

I am trying to simulate an organic ligand docked in the binding site
of a GPCR in an explicit membrane-water system using Amber8. I have
modeled my ligand's carboxylate group as charged (-1). This acidic
group of the ligands is reported in the literature to form a
SALTBRIDGE/H-bond with a protonated Lysine residue sidechain in the
binding site.

Now, the starting complex of my GPCR-Ligand model has several
H-bonding interactions including the above mentioned saltbridge/h-bond
(resulting from: I built this model in vaccum and docked ligands as
reported in PROTEINS 2006, 65, 824-842). Now, I am trying to simulate
this system in membrane environment.

Following are my doubts:

Question 1A: After putting this above starting complex (with all
h-bonds/salt-bridge) in a lipid bilayer, when I perform Molecular
mechanics on this system, SHOULD I RESTRAIN THE PROTONATED NITROGEN
AND CARBOXYLATE GROUP (invloved in saltbridge/h-bond), and also
restrain other putative H-bonding interactions. DOES IT MAKE SENSE TO
GIVE such DISTANCE RESTRAINTS (I have seen some publications which
have used them during MD)

Question 1B: IF I SHOULD USE SUCH DISTANCE RESTRAINTS BETWEEN LIGAND
AND PROTEIN ATOMS, THEN SHOULD THESE RESTRAINTS BE INCLUDED IN all
1,2,3 steps below or just certain of these steps (might sound like a
stupid question, however, wanna make sure):

1. Initial Minimization of System
2. Equilibration MD
3. Production MD

Ofcourse after my production MD, I will minimize the system without
any restraints to check if the h-bonds etc. are stable??

I will look forward to your suggestions.
Thanks and Best Regards

Akshay

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Akshay Patny
PhD Candidate (5th Yr.), Computational Chemistry
Department of Medicinal Chemistry, School of Pharmacy
The University of Mississippi
805 College Hill Rd, # 9, Oxford, MS 38655
E-mail: akshay17_at_olemiss.edu
Phone (O): (662)-915-1286,(M): (662)-801-5496
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