[gmx-users] Simulation with ligand on protein surface

Justin Lemkul jalemkul at vt.edu
Sun Jul 12 03:40:28 CEST 2015

On 7/11/15 2:51 AM, adam zalewski wrote:
> Hi Justin and sorry for the vagueness
> What I'm observing are displacements from the binding site (granted, they are
> quite shallow) and loss of any relation to the experimental data. They also
> happen fairly fast (often below 10ns) and just looking at the trajectory, makes
> me think something is wrong (e.g. a nicely buried phenyl ring being exposed into
> the solvent). Now that you mention it, the ligand parametrization does seem like
> the place to look. Any hints regarding that (acpype/antechamber or otherwise) ?

AMBER parametrization is done relative to QM target data, e.g. RESP fitting.  If 
your phenyl ring is flipping into the solvent, is is probably overly polar. 
Compare its charges against something like Phe.  If the charges are dissimilar, 
you'll have to do a more thorough parametrization of the molecule by targeting 
QM data in the manner prescribed by the force field (and there's lots of 
literature on that).


> Thanks and a nice weekend,
> Adam
> On 07/10/2015 11:09 PM, Justin Lemkul wrote:
>> On 7/10/15 5:02 AM, az wrote:
>>> Hi all
>>> I was wondering if anyone had experience/pointers regarding simulating
>>> protein-ligand systems where the interface was heavily surface-exposed ?
>>> I've been running quite a few of those these days with Amber99SB--ildn, TIP3P,
>>> and acpype (i.e. Ambertools) for ligand parametrization, mainly for the purpose
>>> of probing stability of peptidomimetic docking poses (10-50ns; aside from the
>>> force-field I follow Justin Lemkul's tutorial quite closely). Having however
>>> noticed that some of my reference ligands (i.e. ones with crystallographic/NMR
>>> data) wander away from where they should remain, I started wondering whether
>>> there could be something wrong with my setup. I obviously understand there's a
>>> zillion possibilities here, but I was still wondering whether there exists some
>>> sort of 'good-practice' for such cases (e.g. choice of force-fields,
>>> equilibration protocols ... anything really). I cannot be the only one doing
>>> this and if anyone has a protocol that served them well in the past, I'd love to
>>> learn about it.
>> In general, if an interaction is not preserved, that suggests a poor
>> parametrization of that ligand.  But "wander away" is a bit vague; if it's
>> just a small reorientation or something, it may not actually be "wrong" at
>> all. Depends on the quality of the experimental data and the agreement with
>> experimental conditions, as well.
>> -Justin


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


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