[gmx-users] Creating topology for Cu-containing enzyme, GROMOS96 force field.

[Justin Lemkul]

On 8/10/16 3:26 PM, Francesca Lønstad Bleken wrote:
> I am interested in a metalloenzyme with Cu and I have found several studies
> in the literature on systems similar to mine using GROMACS and the Gromos
> force field. I see that GROMOS contains parameters for Cu, and I intend to
> keep the Cu-protein distances for the ligand atoms fixated during MD (as I
> see most of the previous papers have done). However, I do not understand how
> to prepare the topology for the cofactors with Cu, and none of the papers
> discuss this. pdb2gmx does not recognize it and the PRODRG server suggested
> in the excellent tutorial on protein-ligand system does not recognize Cu. Do
> you have a suggestion for how to proceed with creating the topology including
> Cu (in one case) and Cu-containing (another case) co-factors? Direction
> towards tutorials that I might have missed are also appreciated.
>

This is certainly not a trivial task.  Dealing with metal-containing cofactors 
is a challenge for any MD force field, as most representations of ions 
(particularly divalent ones) is very crude and ultimately incorrect.  You have 
to do proper charge calculations (e.g. QM ESP) to determine what effect the ion 
has on the ligating atoms in the rest of the cofactor.  With the constraint that 
the ion should have an integral charge (ultimately incorrect based on QM/MM, but 
a necessary approximation for additive force fields), the charges have to be 
re-apportioned accordingly.  Given the vague connection between GROMOS force 
fields and QM (most of GROMOS parametrization requires empirical adjustment to 
achieve agreement with condensed-phase thermodynamic data), I would recommend 
using a different force field with more detailed, published parametrization 
protocol, one with a direct connection to QM.  CHARMM, AMBER, and OPLS all have 
very detailed procedures available and are likely better suited to these types 
of species.

-Justin

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Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

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