Re: ABF Questions

From: McGuire, Kelly (mcg05004_at_byui.edu)
Date: Sat Jul 21 2018 - 14:06:51 CDT

Thanks Giacomo, that is good information. Could those additional collective variables all go in the same .in file and be biased simultaneously all in one ABF simulation? Or would these be separate simulations?

Kelly L. McGuire

PhD Scholar

Biophysics

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Giacomo Fiorin <giacomo.fiorin_at_gmail.com>
Sent: Saturday, July 21, 2018 12:44:52 PM
To: NAMD list; McGuire, Kelly
Cc: Jérôme Hénin
Subject: Re: namd-l: ABF Questions

This is a clear sign that you need to include other degrees of freedom (i.e. other collective variables), which are limited by kinetic barriers and need to be biased as well. For a transmembrane channel pore, these can be movements of groups (side chains, or even entire protein domains) that need to get out of the way of the ligand before it can pass. This movement is a rare event, but likely much lower than 50 kcal/mol: that number is corrupted because the orthogonal degrees of freedom do not follow a canonical distribution in your simulation, but ABF (and all other free energy methods, really) assumes that they do.

The solution is highly specific to the system of study: check the literature for this and other similar channels, to see whether what you plan can be done, and how did others treat it. You may have to invest significant effort or computer time, or restrict the investigation to a region of the PMF that can be sampled reliably.

Giacomo

On Sat, Jul 21, 2018 at 10:54 AM McGuire, Kelly <mcg05004_at_byui.edu<mailto:mcg05004_at_byui.edu>> wrote:

Thanks for the response! I'm trying to figure out why the free energy profile of my ion channel and ligand has about 50 kcal/mol higher energy with the ligand exiting into bulk water on the C-terminus side vs exiting the N-terminus side into bulk water. They should be about equal energy, right? That doesn't seem correct...

Kelly L. McGuire

PhD Scholar

Biophysics

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Jérôme Hénin <jerome.henin_at_ibpc.fr<mailto:jerome.henin_at_ibpc.fr>>
Sent: Saturday, July 21, 2018 5:03:39 AM
To: Namd Mailing List; McGuire, Kelly
Subject: Re: namd-l: ABF Questions

On Sat, 21 Jul 2018 at 04:17, McGuire, Kelly <mcg05004_at_byui.edu<mailto:mcg05004_at_byui.edu>> wrote:

Two questions about ABF:

1) Right now I have the center of mass of my ligand as the main atoms and the center of mass of my protein as the ref atoms (i.e. all of the CA C N O atom types of the backbone). But if for my ref atoms I just the center of mass of one of the side chains near the middle of the protein, could this change my PMF results drastically? How critical is the choice of ref atoms within the protein for ABF with a ligand in the protein?

That is actually a question about your protein, not about ABF.

(Is there a limit of atom numbers that can be used for the ref atoms?)

There is no limit. Large numbers will incur a performance penalty, but a few dozens or even a couple hundred should be fine - especially with a center-of-mass-based coordinate.

2) The lowerboundarywall and upperboundarywall are used essentially to keep say a ligand within the specified window, but how much does the choice of value itself have an effect on the PMF result? Would 10 kcal/mol vs 100 kcal/mol for these values have a large effect on my results?

Most likely not. The only case that could be a problem is a PMF that is steeply decreasing towards the boundary, but it is more typically increasing.

Jerome

--
Giacomo Fiorin
Associate Professor of Research, Temple University, Philadelphia, PA
Contractor, National Institutes of Health, Bethesda, MD
http://goo.gl/Q3TBQU
https://github.com/giacomofiorin

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