Re: Parameter Optimization Advice

From: McGuire, Kelly (mcg05004_at_byui.edu)
Date: Fri Mar 01 2019 - 13:42:39 CST

Thanks Josh, I worried about using Gaussian for that purpose. I read a paper where a group used that as standard practice, but I didn't think you could just through in any set of partial charges and trust them.

So, even though FFTK gets partial charges with just water interactions, would it be good practice to try and optimize those charges with other groups of interest? For example, I am interested in histidine (particularly imidazole nitrogen), serine, and asparagine interactions with my ligand. Should I use FFTK to try and optimize charges for those interactions? Problem is, I can only settle for one set of parameters, so if I optimize them for one interaction, they might be wrong for others. Perhaps I am over-thinking this though. Maybe the interactions aren't as bad as I might think they could be.

Kelly L. McGuire

PhD Candidate

Biophysics

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Vermaas, Joshua <Joshua.Vermaas_at_nrel.gov>
Sent: Friday, March 1, 2019 12:36 PM
To: lennart.nilsson_at_ki.se; McGuire, Kelly; namd-l_at_ks.uiuc.edu
Subject: RE: Parameter Optimization Advice

+1

FFTK follows CHARMM-standard advice. FFTK isn't so much trying to parameterize things so that its perfect for your environment, but so that it plays nicely with the rest of the force field. So lets answer your questions:

1.) Partial charges for CHARMM force fields come from calculating water interactions. Nothing else is really considered from what I can tell, other than perhaps some small adjustments to make aliphatic hydrogens exactly 0.09 and whatnot.

2.) If you used Gaussian for your partial charges, you are going to have a bad day when you realize that your electrostatics are not even remotely comparable with the rest of the force field.

3.) As currently implemented, I'm not sure if QM/MM behaves sanely with long-range electrostatics. Leaving that aside, most QM/MM that I see is done at levels of theory that emphasize speed over accuracy, and even then are bottlenecked by the QM component, so there are practical sampling reasons for why QM/MM is usually just saved for when bonds are being made or broken.

-Josh

On 2019-03-01 12:25:16-07:00 owner-namd-l_at_ks.uiuc.edu wrote:

The basic advice is to use the same procedures as were used in developing the parameters of the force field you want to use.

Lennart Nilsson

Karolinska Institutet

From: owner-namd-l_at_ks.uiuc.edu [mailto:owner-namd-l_at_ks.uiuc.edu] On Behalf Of McGuire, Kelly
Sent: den 1 mars 2019 19:13
To: namd-l_at_ks.uiuc.edu
Subject: namd-l: Parameter Optimization Advice

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?

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?

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?

Kelly L. McGuire

PhD Candidate

Biophysics

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

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