Re: Parameter Optimization Advice

From: Brian Radak (brian.radak_at_gmail.com)
Date: Fri Mar 01 2019 - 13:18:15 CST

On Fri, Mar 1, 2019 at 1:14 PM McGuire, Kelly <mcg05004_at_byui.edu> wrote:

> I have gone through and used the FFTK parameter optimization for new
> molecules to simulate in NAMD. I have also used Gaussian independently of
> FFTK to get some parameters. I am trying to get a feel for best parameter
> optimization practices. Here are the questions I have though:
>
> 1) FFTK is mostly used to optimize water-molecule interactions and
> parameters, correct? But, if the molecule is in a semi-vacuum environment,
> say an ion channel, that has anywhere from 20-100 water molecules, then the
> molecule is probably interacting more with the sidechains and a vacuum
> environment than a bulk water environment. Does the FFTK optimization
> process do anything for interactions other than water molecules?
>
> This is a good point, and might warrant tests with ligands other than
water. You can always make additional adjustments in order to best
reproduce the energies and geometries that you think are most important.
I'm not 100% sure what you mean by vacuum environment, but it's very
difficult/impossible to have fixed partial charges that work well in gas
and condensed phase since the nature of polarization is so different.

> 2) Partial charges are fixed in MD simulations, so even if I used a
> program like Gaussian to get good partial charges and then put those in my
> parameter files, how much can I trust and energy calculation process such
> as adaptive biasing force free energy profiles? In other words, can my
> choice of partial charges greatly effect my MD simulations? And, what
> process do you recommend for optimizing parameters?
>
> Without any testing, it's arguable that you shouldn't trust any partial
charges of any kind. Try a simple problem and see if the results are
qualitatively or semi-quantitatively inline with experiments. The specific
charges may or may not greatly affect the answer (that might be an
interesting result in itself!) and balancing Coulombic against
Lennard-Jones interactions is the one of the most difficult problems in
force field design. The CHARMM and FFTK philosophy is generally to get
geometries and interaction energies correct, whereas the AMBER philosophy
is to get the electrostatic potential correct and then separately adjust
Lennard-Jones.

> 3) If QM/MM can be done, is that always the better choice because the
> interactions will be more accurate for the QM region/region of interest?
> In the QM region, do partial charges change, or are they still fixed during
> the simulation?
>
> It's a huge mistake to assume that QM is always more accurate than MM.
There are all kinds of QM models, and especially QM/MM models, that are
qualitatively incorrect compared to experiment (especially semiempirical
methods). The only time QM is (trivially) guaranteed to be better is when
bonds are breaking/forming. The most common implementations of QM/MM
(electrostatic embedding) do include polarization and charge transfer in
response to the MM region, but this is one-sided and thus has its own
potential flaws.

>
>
> *Kelly L. McGuire*
>
> *PhD Candidate*
>
> *Biophysics*
>
> *Department of Physiology and Developmental Biology*
>
> *Brigham Young University*
>
> *LSB 3050*
>
> *Provo, UT 84602*
>
>
>

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