[gmx-users] Energy minimisation goes to several values

[Kevin C Chan]

Thanks Justin again for the reply.

Your example was very clear and I would rather drop such minimization protocol. Honestly such protocol comes from the conventional step-wise relaxation (or pre-equilibrium) practice for protein MD simulations. I believe you must have heard people constraining heavy atoms (carbon alpha atoms or sometimes even the backbone) during heating, box relaxation and then releasing them by decreasing the spring constant step-by-step before they started a production on the protein. So how do you comment on this stepwise protocol? If it is applicable, should it be turned on during energy minimization or just started from heating?

Thanks in advance,
Kevin


> On 27 Jun, 2015, at 07:54, <gromacs.org_gmx-users-request at maillist.sys.kth.se> <gromacs.org_gmx-users-request at maillist.sys.kth.se> wrote:
> 
> From: Justin Lemkul <jalemkul at vt.edu <mailto:jalemkul at vt.edu>>
> Subject: Re: [gmx-users] Energy minimisation goes to several values
> Date: 27 June, 2015 07:54:13 HKT
> To: Discussion list for GROMACS users <gmx-users at gromacs.org <mailto:gmx-users at gromacs.org>>
> Reply-To: <gmx-users at gromacs.org <mailto:gmx-users at gromacs.org>>
> 
> 
> 
> 
> On 6/26/15 11:54 AM, Kevin C Chan wrote:
>> Thanks Justin for the reply.
>> 
>> Honestly I thought minimizing a large and complex (usually biomolecular) system
>> part by part instead of as a whole will effectively shorten the computational
>> time cost while causing no effect on the final structure. When you say
>> “impedes”, do you mean it causes a longer calculation time in total or it will
>> give a bad final structure?
>> 
> 
> Well, you're running three minimizations instead of one, and you're achieving an unstable result.  I'd say the three-step approach is not worth doing :)
> 
> Consider something really simple - a polar, surface residue on a protein surrounded by water.  Let's say you freeze the protein and let the water relax.  The local waters respond to the fixed geometry of the side chain, which is (maybe) from a crystal and therefore perhaps not the correct conformation in solution.  So the waters reorganize a bit.  Then you let the protein relax but the waters are fixed.  The side chain responds to a fixed clathrate of water that have been minimized around the wrong side chain conformation.  What have you achieved?  Nothing.  Sure, you then minimize the whole system, but your starting point is potentially less plausible than it was to start with!  At minimum, it's just a waste of time.  Occasional use of restraints can be beneficial in some cases.  Any time you talk about absolutely fixing large groups of atoms (like immobilizing water), I think it's really a waste of time.
> 
> If a single, unrestrained minimization still leads to an unstable system, then it's not your minimization protocol that's to blame, rather an unresolvable starting structure or a bad topology.
> 
> -Justin
> 
>> Thanks in advance,
>> Kevin
>> 
>>> On 26 Jun, 2015, at 22:21, <gromacs.org_gmx-users-request at maillist.sys.kth.se <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se>
>>> <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se>>>
>>> <gromacs.org_gmx-users-request at maillist.sys.kth.se <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se>
>>> <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se <mailto:gromacs.org_gmx-users-request at maillist.sys.kth.se>>> wrote:
>>> 
>>> *From:*Justin Lemkul <jalemkul at vt.edu <mailto:jalemkul at vt.edu> <mailto:jalemkul at vt.edu <mailto:jalemkul at vt.edu>>>
>>> *Subject:**Re: [gmx-users] Energy minimisation goes to several values*
>>> *Date:*26 June, 2015 21:27:32 HKT
>>> *To:*<gmx-users at gromacs.org <mailto:gmx-users at gromacs.org> <mailto:gmx-users at gromacs.org <mailto:gmx-users at gromacs.org>>>
>>> *Reply-To:*<gmx-users at gromacs.org <mailto:gmx-users at gromacs.org> <mailto:gmx-users at gromacs.org <mailto:gmx-users at gromacs.org>>>
>>> 
>>> 
>>> 
>>> 
>>> On 6/25/15 9:45 PM, Kevin C Chan wrote:
>>>> Dear Users,
>>>> 
>>>> I am energy minimising a quite large solvated system containing protein and
>>>> lipids (~800,000 atoms). I used to fix components of the system in order to
>>>> speed-up energy minimisation and sometimes it is easier to debug such
>>>> processes. Here is my protocol:
>>>> 1. fix all except water and so to minimise water
>>>> 2. fix water and then minimise all the rest atoms
>>>> 3. fix nothin and then minimise the whole system
>>>> 
>>>> While monitoring the energy of the system thought minimisations, it goes
>>>> fine for step 1 and 2 and converged after just few hundred steps. However
>>>> it goes back to several higher values of energy (bouncing between the
>>>> values) and they started to increase very slowly for step 3. This makes no
>>>> sense to me and did anyone have a similar experience?
>>>> 
>>>> There are two unusual points:
>>>> 1. The system energy drops suddenly instead of decreased gradually during
>>>> step2 and then stays at a constant value.
>>>> 2. If I use the resulting structure from step3 to proceed a, say, heating
>>>> process, it simply blows up.
>>>> 
>>>> To be clear, my system was solvated and auto-ionized using VMD tools and
>>>> some water inside the membrane has been directly deleted. Backbone of the
>>>> protein and phosphorus atoms of the membrane are under a
>>>> position constraint during all the minimisations. I was choosing conjugate
>>>> gradient for minimization.
>>>> 
>>> 
>>> Does a "normal" minimization (just one overall minimization with nothing
>>> fixed) yield a stable starting point?  Fixing atoms (using freezegrps?) often
>>> actually impedes minimization.
>>> 
>>> -Justin
>>> 
>>> --
>>> ==================================================
>>> 
>>> Justin A. Lemkul, Ph.D.
>>> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>>> 
>>> Department of Pharmaceutical Sciences
>>> School of Pharmacy
>>> Health Sciences Facility II, Room 629
>>> University of Maryland, Baltimore
>>> 20 Penn St.
>>> Baltimore, MD 21201
>>> 
>>> jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu> <mailto:jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu>>|
>>> (410) 706-7441
>>> http://mackerell.umaryland.edu/~jalemkul <http://mackerell.umaryland.edu/~jalemkul>
>>> 
>>> ==================================================
>> 
> 
> -- 
> ==================================================
> 
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
> 
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
> 
> jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu> | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul <http://mackerell.umaryland.edu/~jalemkul>
> 
> ==================================================