I forgot to mention that I'm not growing sites out of nothing nor annihilating them...I'm transforming a hydrogen to a methyl. Actually, I was doing the opposite (changing the methyl to a hydrogen), thinking that might be more forgiving.
What's a typical value that people use for the soft core parameter?
Also, David M., when you recommended not running the simulations sequentially, what exactly did you mean? Something other than the sequence lambda = 0, 0.05, 0.1, 0.15...?
Thanks,
Jonathan
____________________________
Jonathan Moore, Ph.D.
Research and Engineering Sciences - New Products
Core R&D
The Dow Chemical Company
1702 Building, Office 4E
Midland, MI 48674 USA
Phone: (989) 636-9765
Fax: (989) 636-4019
E Mail: jmoore2 at dow.com
-----Original Message-----
From: gmx-users-bounces at gromacs.org [mailto:gmx-users-bounces at gromacs.org] On Behalf Of Moore, Jonathan (J)
Sent: Friday, November 11, 2005 3:56 PM
To: 'Discussion list for GROMACS users'
Subject: RE: [gmx-users] free energy calculations blowing up
David and David,
Thanks for the suggestions. I'm not currently using soft cores for fear of the soft core bug in 3.2.1. http://www.gromacs.org/pipermail/gmx-users/2004-August/011830.html
I haven't moved to 3.3 yet on any of my production machines because I'm holding out for 3.3.1, but maybe I'll have to give up waiting so I can use soft cores.
David M., I guess this is the paper you were talking about, right? T. C. Beutler, A. E. Mark, R. C. van Schaik, P. R. Gerber and W. F. van Gunsteren. "Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations." Chem. Phys. Lett., 222, 529-539 (1994).
http://dx.doi.org/10.1016/0009-2614(94)00397-1
Thanks,
Jonathan
____________________________
Jonathan Moore, Ph.D.
Research and Engineering Sciences - New Products
Core R&D
The Dow Chemical Company
1702 Building, Office 4E
Midland, MI 48674 USA
Phone: (989) 636-9765
Fax: (989) 636-4019
E Mail: jmoore2 at dow.com
-----Original Message-----
From: David Mobley [mailto:dmobley at gmail.com]
Sent: Friday, November 11, 2005 3:27 PM
To: Discussion list for GROMACS users
Subject: Re: [gmx-users] free energy calculations blowing up
Jonathan,
To clarify slightly, the singularity for lambda->1 is when the lambda=1 Hamiltonian corresponds to a completely disappeared particle. If you are changing on vdW radii into another vdW radii things are somewhat more complicated and it isn't clear to me that you really have the same sort of problem. I wouldn't be surprised if you did, though, but it would be at some intermediate lambda value. I would still try the soft core option, especially if your time series of dV/dlambda have anything that looks at all like shot noise.
David
On 11/11/05, David Mobley <dmobley at gmail.com> wrote:
Jonathan,
Two comments:
(1) Although this wasn't your question, you might not want to run the simulations sequentially. I think previous work has shown that you can introduce some hysteresis this way, although the reference eludes me at the moment.
(2) When changing vdW parameters, soft core helps a lot. From what you're describing it sounds like you are doing that. If you don't use soft core, dV/dlambda actually has a singularity for particle insertion as lambda->1 (assuming the exponent of lambda is 1, which it is by default) and is also very susceptible to shot-type noise, and susceptible to crashes when forces get too large (which often happens near lambda=1). You can reduce the crashes somewhat by using smaller timesteps but this doesn't help with the shot noise or singularity problems. To understand why this happens you can look up van Gunsteren's paper from around 1992 introducing the soft core potential, or contact me directly for a brief explanation. If you have any trouble finding the reference I can look it up for you, but I don't have it in front of me right this instant.
David Mobley
UCSF
On 11/11/05, Moore, Jonathan (J) <JMoore2 at dow.com > wrote:
I have a question about free energy calculations.
I'm performing several different simulations where the hydrogen of certain hydroxyls on my molecule is replaced with a methyl group. It's a united atom model, so the change from hydrogen to methyl doesn't change the number of sites. I have a single molecule of interest in SPC water (see more details below). I'm experiencing the problem that on occasion the system blows up. I've had no problems like this previously when simulating only one state or the other (methylated or unmethylated), so I think the problem is due to the free energy calculation. Unless I've made an error in setting up the free energy calculation, I assume my problem is that the system isn't stable for the timestep that I'm using (2 fs) and how fast I'm changing lambda (I'm incrementing lambda by 0.05 followed by 200 ps of simulation before increasing it again).
Is it common to either decrease the time step or use lambda increments smaller than 0.05 when doing free energy calculations this way? I'm planning to try both to see if they fix the problem, but I'm curious if anyone else has had a problem like this. I'm not using soft cores, but maybe I have to?
Also, I'm specifying the atom types like this (i.e., with the mass being taken from the .atp file):
[ atoms ]
; nr type resnr residu atom cgnr charge
6 H 1 H000 HO3 2 0.410
Therefore, when I specify the B state, I do it like this (i.e. with out specifying the change in mass, assuming the GROMACS will also get the B state mass properly from the .atp file):
[ atoms ]
; nr type resnr residu atom cgnr charge
6 H 1 H000 HO3 2 0.410 CH3 0.180
Should that work OK? It wasn't obvious to me where to look in the output to make sure it is. I assume I'll be able to answer that question myself when 3.3.1 is released and I can use "gmxcheck -ab"
More details:
v. 3.2.1, single precision
2 fs timestep
All bond lengths constrained (LINCS)
Nosé-Hoover thermostat with the polymer and solvent coupled separately; 0.4 ps time constant Berendsen barostat with 0.5 ps time constant and 4.5x10-5 bar -1 compressibility Triple-range cut-off method
Thanks,
Jonathan
____________________________
Jonathan Moore, Ph.D .
Research and Engineering Sciences - New Products
Core R&D
The Dow Chemical Company
1702 Building, Office 4E
Midland, MI 48674 USA
Phone: (989) 636-9765
Fax: (989) 636-4019
E Mail: jmoore2 at dow.com
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