Re: Colvars Restraint Question

From: McGuire, Kelly (mcg05004_at_byui.edu)
Date: Sun Jun 24 2018 - 23:20:31 CDT

Joshua, I am running my ABF without the restraint on the center-of-mass and to trust the force field like you said. A question while it finishes:

  How does diffusion of the membrane and the protein in the membrane effect the result of the ABF with the ligand? For example, if the membrane and protein diffuse downwards, it will potentially pull on the ligand (which may happen in reality), but as far as the jerking motion potentially changing the reaction coordinate at times during the simulation/calculation, would that have an effect on the result? I hope that question was clear, thanks!

Kelly L. McGuire

PhD Scholar

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Vermaas, Joshua <Joshua.Vermaas_at_nrel.gov>
Sent: Thursday, June 21, 2018 3:02:54 PM
To: McGuire, Kelly; brian.radak_at_gmail.com
Cc: bhaddad_at_pdx.edu; namd-l_at_ks.uiuc.edu
Subject: RE: namd-l: Colvars Restraint Question

Hi Kelly,

Its clear enough. What I think is happening is that you are just simply asking alot from only 10ns of sampling. Usually, when using umbrella sampling, I've only really only started getting converged simulations for similar systems at that time, and only if your windows are separated by 0.5-1 Angstrom, rather than 5. Perhaps someone with more ABF experience would have more useful insight, but to me the most effective remedy is just to make your windows smaller and to have more of them. It is also possible that you just need to run longer.

Now lets talk about restraints. The restraints on your protein are likely not required, since the reaction coordinate you describe doesn't care in the slightest about protein translation within the membrane. Trust in the force field, and try not to bias your system too strongly, since natural conditions won't have those restraints.

-Josh

On 2018-06-21 14:46:55-06:00 McGuire, Kelly wrote:

I have a ligand (amantadine) in this protein (homotetramer), and I have it start at the center of mass of the histidine side chains, with the amine of the amantadine pointing down (negative z direction). The reaction coordinate is the distance from the histidine side chains' center of mass to the amine of the amantadine. I have 5 windows of 5 angstrom boundaries.

So, the amine of the amantadine starts zero angstroms from the His COM (z-coordinate) for the first window, and the boundaries are -2.5 and 2.5. In the second window, the amantadine has been translated +5 angstroms in the z direction, and the boundaries of that window are 2.6 and 7.6. Third window, another +5 angstrom translation in the z direction, and boundaries are 7.7 and 12.7. Fourth window, another +5 angstrom translation, boundaries are 12.8 to 17.8. And, fifth window, a +5 angstrom translation, and boundaries are 17.9 to 22.9. The amantadine ends up being 25 angstroms from the COM of the His side chains in the last window, and into bulk water.

We noticed that the amantadine doesn't explore most of the windows in our simulations of 10 ns per window, so I end up with a lot of zeroes in the .count files, which is a problem for calculating the pmf. I get a lot of flat plateaus...

We thought maybe the amantadine isn't getting around the side chains because the backbone is too rigid with a restraint placed on it...therefore, we decided on a center of mass restraint.

I hope that helps clarify some of our thinking...maybe not though lol.

The overall shape of the PMF is what we expect relative to previous umbrella sampling results, but the depths and heights of the wells/barriers are quite different...

Kelly L. McGuire

PhD Scholar

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Vermaas, Joshua <Joshua.Vermaas_at_nrel.gov>
Sent: Thursday, June 21, 2018 2:22:10 PM
To: McGuire, Kelly; brian.radak_at_gmail.com
Cc: bhaddad_at_pdx.edu; namd-l_at_ks.uiuc.edu
Subject: RE: namd-l: Colvars Restraint Question
Hi Kelly,

I'm not clear why you want to restrain the protein within the bilayer. If it is a normal membrane-embedded protein, they certainly won't spontaneously leave the membrane, so a restraint would be entirely superfluous. In previous simulations, where we cared about a small molecule entering a bilayer and we cared about the distance along the membrane normal (distanceZ), we would just compute that distance relative to a selection of atoms at the center of the membrane (main would be the small molecule, ref would be the lipid tails). What reaction coordinate are you ABFing?

-Josh

On 2018-06-21 14:08:00-06:00 owner-namd-l_at_ks.uiuc.edu wrote:

I see, we want to restrain the protein in the bilayer, but not with the restraint on the backbone or alpha carbons, because we

want the protein backbone to be flexible and be able to open up or close during the simulation...

Kelly L. McGuire

PhD Scholar

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

________________________________
From: Brian Radak <brian.radak_at_gmail.com>
Sent: Thursday, June 21, 2018 2:01:39 PM
To: McGuire, Kelly
Cc: namd-l; Bassam Haddad
Subject: Re: namd-l: Colvars Restraint Question
Oh, I was unaware that dummyAtom was a built-in colvars function - very cool and convenient.
Ultimately the selection you make depends completely on why you want to have a COM restraint. The previous response from Jerome seems to indicate someone who wanted to define another colvar with respect to a frame of reference that they wanted to remain intact. It would seem that covars can do this automatically in many instances without recourse to an additional translational bias.

On Thu, Jun 21, 2018 at 3:53 PM, McGuire, Kelly <mcg05004_at_byui.edu<mailto:mcg05004_at_byui.edu>> wrote:

Hmmm, I was going off of this response in the mailing list, this is where I got the idea for the

dummy atom:

http://www.ks.uiuc.edu/Research/namd/mailing_list/namd-l.2013-2014/0768.html%7C17940ec9224247eaa1cf08d5d7b2aed1%7Ca0f29d7e28cd4f5484427885aee7c080%7C0%7C0%7C636652084800677131&sdata=XBUy5W3MKBTCUdRKJny8TcTI9M03KPYdkBSiWjjn9Eo%3D&reserved=0>

namd-l: Re: How to remove center of mass translation of ...<https://na01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.ks.uiuc.edu%2FResearch%2Fnamd%2Fmailing_list%2Fnamd-l.2013-2014%2F0768.html&data=02%7C01%7CJoshua.Vermaas%40nrel.gov%7C17940ec9224247eaa1cf08d5d7b2aed1%7Ca0f29d7e28cd4f5484427885aee7c080%7C0%7C0%7C636652084800677131&sdata=XBUy5W3MKBTCUdRKJny8TcTI9M03KPYdkBSiWjjn9Eo%3D&reserved=0>
www.ks.uiuc.edu<https://na01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.ks.uiuc.edu&data=02%7C01%7CJoshua.Vermaas%40nrel.gov%7C17940ec9224247eaa1cf08d5d7b2aed1%7Ca0f29d7e28cd4f5484427885aee7c080%7C0%7C0%7C636652084800687140&sdata=OUrW4LYzrXym6n8Asngl2q299LHJmtJivS%2BfDPo1j54%3D&reserved=0>
Re: How to remove center of mass translation of macromolecule. From: Jérôme Hénin (jerome.henin_at_ibpc.fr<https://na01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fjerome.henin_at_ibpc.fr&data=02%7C01%7CJoshua.Vermaas%40nrel.gov%7C17940ec9224247eaa1cf08d5d7b2aed1%7Ca0f29d7e28cd4f5484427885aee7c080%7C0%7C0%7C636652084800687140&sdata=nAzI0qGugRPeeAcQ6Hr04bjNuEOwukwcZW7rg5LSeF8%3D&reserved=0>) Date: Wed Jun 12 2013 - 04:00:48 CDT Next message: Shubhra Ghosh Dastidar: "Error while running the infiniband version."

I was worried though that I would have to type every serial atom number for the membrane and protein into one of

the groups...

Kelly L. McGuire PhD Scholar Department of Physiology and Developmental Biology Brigham Young University LSB 3050 Provo, UT 84602
________________________________
From: Brian Radak <brian.radak_at_gmail.com<mailto:brian.radak_at_gmail.com>>
Sent: Thursday, June 21, 2018 1:01:23 PM
To: namd-l; McGuire, Kelly
Cc: Bassam Haddad

Subject: Re: namd-l: Colvars Restraint Question
This should be pretty clear from the user's guide.
Harmonic center of mass restraints operate on a scalar distance. The first group is not anchored to a fixed point but rather to another point defined by another group. I don't know the standard practice, but defining group 2 as a dummy atom experiencing no forces and with no velocity would constitute a fixed point. Maybe use fixedAtoms?
Also, you should generally keep center of mass selections as small as possible for performance purposes.

On Thu, Jun 21, 2018 at 2:43 PM, McGuire, Kelly <mcg05004_at_byui.edu<mailto:mcg05004_at_byui.edu>> wrote:

How about in the colvars file though where I select two groups, one being the center of mass for the

protein-bilayer system and then a dummy atom...? In the group with the lipids/protein, would I just

list all of the serial atom numbers or residue names...?

Kelly L. McGuire PhD Scholar Department of Physiology and Developmental Biology Brigham Young University LSB 3050 Provo, UT 84602
________________________________
From: Bassam Haddad <bhaddad_at_pdx.edu<mailto:bhaddad_at_pdx.edu>>
Sent: Thursday, June 21, 2018 11:33:58 AM
To: namd-l_at_ks.uiuc.edu<mailto:namd-l_at_ks.uiuc.edu>; McGuire, Kelly
Subject: Re: namd-l: Colvars Restraint Question
Hi Kelly,
I think your atom selection in vmd would be...
set sel [atomselect top "lipids or protein"]
Bassam

On Thu, Jun 21, 2018 at 10:05 AM McGuire, Kelly <mcg05004_at_byui.edu<mailto:mcg05004_at_byui.edu>> wrote:

I would like to place a harmonic restraint on the center of mass of a protein-membrane system. I have an ion channel

in a bilayer, and I would like to restrain the COM of that system during my adaptive biasing force simulation. What would

the atom selection look like in order to create that restraint?

Kelly L. McGuire

PhD Scholar

Department of Physiology and Developmental Biology

Brigham Young University

LSB 3050

Provo, UT 84602

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