Re: [AMBER] optimise ligand geomatry before MD

From: Karl Kirschner <>
Date: Wed, 29 Jan 2014 10:13:53 +0100

Hello Nitin,

  Yes, in general one should optimize a ligand's geometry prior to an MD
simulation. If the force-field parameters are present and trustworthy, then
performing an MM minimization is sufficient. This is important so that you
do not introduce artificially large forces, arising from the molecule
residing at a high energy state on the MM's potential energy surface, at
the start of your simulation.

  However, if the parameters are not present (e.g. torsion terms, partial
atomic charges) then you will need to optimize the ligand using QM or
Antechamber (i.e. sqm). Most Amber force fields were developed with
geometries optimized at HF/6-31G(d), but many use the Antechamber/sqm
method for optimizing ligands, which I believe is semiempirical. Both
methods are comparable, in the sense that they optimize the geometry, but
differ in the theory used to do so. Different theories will lead to
different optimized geometries, sometimes they have relatively minor
differences (e.g. bond distances) and sometimes they are more significant
(e.g. different rotamers).

  Once you have the optimized conformation, then you use it as an input to
determine partial atomic charges. There is quite a bit of literature for
this already present for Amber, including using multiple conformations to
determine a single charge set for a molecule.

  It is reasonable/necessary to optimize a ligand's conformation that you
obtained from a docking pose. If you used flexible docking methods, then
note that this conformation may change due to the absence of the binding

  As for websites/methods that you can use, Antechamber's can perform an
optimization (via sqm) and to determine partial atomic charges. The R.E.D.
website will also allow you to do both in a manner that is balanced with
the Amber force fields. You can also have the option of downloading a
number of QM software packages, such as Gamess and Gaussian. I would
suggest doing some more reading regarding partial atomic charge
determination and ligand/residue model building (e.g. Parm94, Gaff,
Glycam06, R.E.D., Wolf2Pack, etc. papers).

Best regards,

On Tue, Jan 28, 2014 at 7:44 PM, Nitin Sharma <>wrote:

> Dear amber users,
> Is it necessary to optimize ligand geometry before molecular dynamics
> simulation?
> I am using AMBER for MD simulation.
> I have seen studies where ligand was parameterized according to quantum
> chemical calculations, which included performing a geometry optimization
> with Gaussian98
> at the Hartree-Fock/6-31G* level before determining atomic charges and
> atomic types using Antechamber module of the Amber molecular dynamics
> software package.
> However, i have seen studies where ligand were assigned generalized Amber
> force field (GAFF) atom types and AM1-BCC atomic charges obtained by adding
> the bond charge correction (BCC) using Antechamber.
> Are both protocols comparable ?
> As i am thinking to use pose generated as result of docking will the
> ligand geometry optimization be good idea?
> can someone also tell me web-server or software to do ligand geometry
> optimization for AMBER MD simulation
> Thanks and regards,
> Nitin Sharma
> Department of Pharmacy,Faculty of Science,National University of
> Singapore,block S7, Level 2, Singapore :<mailto:
>> ;
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Received on Wed Jan 29 2014 - 01:30:03 PST
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