From: Daniel Fellner (
Date: Mon Apr 04 2022 - 02:04:40 CDT

I've found this to be the case with quite a few drug-like compounds,
particularly ligands for the more lipophilic receptors (cannabinoid,
steroid hormone, etc.). Just a few technical questions: Do all the heavy
atom charges need to be optimised in order to ensure internal consistency?
Or, is it okay to leave some charges which were derived by
water-interactions (presumably) from CGenFF? Some of these charges have low
penalties/low deviations from the QM data.

I did check the NPA charges using HF/6-31G* v.s. wB97X-D/6-311+G** and
there is very little difference, so probably no need to change at this
point (unless it's what's causing me issues in the bonded optimisation...)

In terms of the philosophy, the optimised parameters should reproduce
accurately the PMF of the drug binding. It's a very lipophilic compound -
mostly partitioned into membrane so water interactions aren't critical.
They should also help distinguish the conformational energies for the
purpose of med chem... I'll compare the conformational energies between QM
and MM conformers to validate the latter, and we can get an IR spectrum to
help validate the bonded parameters as well. When it comes to partial
charges though, I'm not sure how I would go about validating those.

One last question: I noticed when optimising the bonded parameters that as
the objective function decreases/converges, the distance of the equilibrium
bond lengths/angles from the QM values increases! Does this behaviour make
sense? I have tried weighting the geometry higher and tightening the
deviation thresholds, but they seem to make little to no difference.

Thanks again,

*Daniel Fellner BSc(Hons)*
PhD Candidate
School of Chemical Sciences
University of Auckland
Ph +64211605326

On Mon, 4 Apr 2022 at 08:41, Gumbart, JC <> wrote:

> There was literally no way to do it with the water-interaction approach
> for a number of atoms in that molecule, so we just had to do what we
> could. We did indeed fix some hydrogen charges according to standard
> CHARMM style.
> With regards to the QM method, I don’t think you need to stick with HF,
> necessarily? Play around and see how sensitive the numbers are to this
> choice. You need to decide what you’re optimizing for, which will be the
> real test of whether it worked or not.
> Best,
> JC
> On Apr 1, 2022, at 3:52 AM, Daniel Fellner <>
> wrote:
> Oh great, thanks! I didn't realise RESP was suitable for deriving
> CHARMM-compatible partial charges. I did notice FFTK has a RESP option now
> but I thought it was just for AMBER.
> I assume the procedure is to put static restraints on the aliphatic and
> aromatic hydrogens not adjacent to a heteroatom (as per CHARMM protocol)
> and to any atoms you don't need to optimise? I gave it a try just now, and
> it does a good job for most atoms, though I do notice some unphysical
> charges on the buried atoms. I guess I'll set these with NPA first.
> Regarding the QM level of theory, should I stick to the default HF/6-31G*
> for both the RESP and NPA calculations? My molecule is neutral and contains
> only C, H, N, F, O atoms unlike the metal complexes in your paper.
> Thanks again for your help,
> *Daniel Fellner BSc(Hons)*
> PhD Candidate
> School of Chemical Sciences
> University of Auckland
> Ph +64211605326
> On Fri, 1 Apr 2022 at 04:51, Gumbart, JC <>
> wrote:
>> With regards to your first question, yes, absolutely it helps. But if an
>> atom is completely buried, it’s definitely less sensitive to the water
>> interactions, but not completely immune. The danger though is that it ends
>> up as a “dumping ground” for excess charge while the more accessible atoms
>> get optimized. Note that RESP suffers from the same problem. We discussed
>> such challenges in this paper:
>> We ultimately settled on a combination of RESP and Natural Population
>> Analysis, with the latter for the buried charges.
>> Best,
>> JC
>> On Mar 30, 2022, at 3:13 AM, Daniel Fellner <>
>> wrote:
>> Just had a few questions about charge optimisation for a difficult
>> substrate.
>> If the atom in question is entirely solvent-inaccessible but has
>> hydrogens attached, does the inclusion of target data from those hydrogens
>> aid in fitting the occluded atom? I've seen this done in the EtOH tutorial
>> but have read conflicting information.
>> As for occluded atoms with no hydrogens attached, how can these be
>> optimised? The highest penalties in my compound are on entirely occluded
>> (SASA <0.020 nm^2/mol) atoms. Is there any sense including them in the
>> charges to be optimised without any target data?
>> *Daniel Fellner BSc(Hons)*
>> PhD Candidate
>> School of Chemical Sciences
>> University of Auckland
>> Ph +64211605326