VMD-L Mailing List

From: Daniel Fellner (dfel694_at_aucklanduni.ac.nz)
Date: Thu Apr 07 2022 - 03:12:01 CDT

Sure, that makes sense.

Re: PMF I meant the PES along the ligand binding/unbinding pathway, which
I'll be sampling with Funnel MetaD, ultimately to obtain a binding free
energy. I wouldn't be able to parameterise based on that, it's rather
expensive. What I meant was that accurate protein-ligand interactions are
what I'd like to achieve.

To be clear, do you mean the MM values in the minimized structure or the
> values in the parameter file?
>

I mean the values from the QM-minimised geometry v.s. the equilibrium
lengths/angles in the parameter file. I suppose because the angles in my
system are highly correlated these may not necessarily match very well. I
suppose checking the MM-minimised lengths/angles v.s. QM ones would be more
meaningful.

Overthinking is a bad habit of mine, but thanks for all the help! I think
I've got it now.

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

On Thu, 7 Apr 2022 at 14:21, Gumbart, JC <gumbart_at_physics.gatech.edu> wrote:

> I’m not sure you need to be internally consistent with how the charges are
> derived. It makes sense for water-accessible ones to follow the CHARMM
> style if possible but then it’s probably much less important for
> inaccessible ones.
>
> You say PMF of drug binding, but no experiment gives a PMF (well, except
> maybe AFM), so I assume you mean binding free energy, or maybe even just
> the Kd. I don’t think you can parameterize based on this alone though, but
> your idea to use conformational energies and IR spectra is good.
>
> 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.
>
>
> To be clear, do you mean the MM values in the minimized structure or the
> values in the parameter file? These are unlikely to be identical for
> anything other than the simplest molecules.
>
> But anyway, don’t overthink it! Just do the best you can in the time you
> have.
>
> Best,
> JC
>
> On Apr 4, 2022, at 3:04 AM, Daniel Fellner <dfel694_at_aucklanduni.ac.nz>
> wrote:
>
> 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 <gumbart_at_physics.gatech.edu>
> 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 <dfel694_at_aucklanduni.ac.nz>
>> 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 <gumbart_at_physics.gatech.edu>
>> 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:
>>> https://urldefense.com/v3/__https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980237/__;!!DZ3fjg!t3TGuD3Yp3jnPqljJCOY0UNEmaUbCyDxXC_1-c0pvWQdR5KNpomRiJZQV7qpXFWp-A$
>>>
>>> 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 <dfel694_at_aucklanduni.ac.nz>
>>> 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
>>>
>>>
>>>
>>
>