[gmx-users] on non-equilibrium MD

[Justin Lemkul]

On 4/3/16 5:09 AM, Brett wrote:
> Dear,
>
>
>
> I am still confisued,
>
>
> Suppose for a protein, its ligand binding form has a higher energy that its
> apo form. After we got the apo format PDB from the protein-ligand PDB, we
> energy minimized the apo protein and equlibrated it and then run production
> MD on it.
>
>
> I deduce if the final stabilized apo protein has significant different
> conformation from the ligand binding status, during the production MD the
> internal energy of the apo protein will change significantly. If the
> production MD cannot cross energy barrier, then how production MD can make us
> see significant protein conformational change during the MD?
>

This is what I said before in reply to your previous question: there is no 
thermal energy in *energy minimization*, therefore you won't see much structural 
change.  But if you run MD (during which you can jump over some energy barriers) 
for long enough, you can see the transition, provided the force field is good, 
sampling is sufficient, chosen algorithms are reasonable, etc.

-Justin

>
> Brett
>
>
>
>
>
>
>
>
>
>
>
> At 2016-04-03 01:08:19, "Justin Lemkul" <jalemkul at vt.edu> wrote:
>>
>>
>> On 4/1/16 10:51 PM, Brett wrote:
>>> Thanks Justin.
>>>
>>> Based on your answer, here I would like to ask,
>>>
>>> Suppose there is a PDB for a protein-ligand, and it is already known
>>> ligand would lead extremely significant conformation change of that
>>> specific protein. Based on the protein-ligand PDB, I would like to
>>> investigate the conformation of the protein without ligand by MD.
>>>
>>> First from the PDB for  the protein-ligand, I delete the ligand part and
>>> get the PDB for the protein part. Then with the protein part PDB and
>>> based on your lyzoyme tutorial protocol, through energy minimization, NVT
>>> and NPT equilibration, I start the production MD.
>>>
>>> Here my question is, as for the energy of the protein in the ligand
>>> binding and ligand free state is significantly different, and based on my
>>> practice based on your lysozyme tutorial, the energy minimization, NVT
>>> and NPT equilibration steps could almost lead to no conformation change
>>> of the protein from the initial PDB conformation in the protein-ligand
>>> state, then
>>
>> As is their purpose.
>>
>>> in the production MD process, there should be a significant conformation
>>> change, which I regard that the conformation change can be checked by
>>> the energy change by command "gmx energy -f md_01.edr -o potential.xvg".
>>> If the
>>
>> The potential energy will be dominated by water, and the potential energy
>> of the protein itself is a force field-dependent, nonphysical quantity.  So
>> no, this doesn't give you anything useful.
>>
>>> protein conformation in the ligand binding status has much higher energy
>>> than in the ligand free state, then will you please tell me why the
>>> conformation change can only be observed in the production md process,
>>> but not in the initial energy minimization step before the production
>>> MD?
>>>
>>
>> There is no thermal energy in EM, so energy barriers are not crossed.  The
>> structural changes are all downhill in local minima.  So to observe
>> conformational changes in an apo protein will require extensive (and
>> multiple) simulations to observe, perhaps on the microsecond scale or
>> longer.
>>
>> You can't simply skip equilibration because you know the structure will
>> change. You still need to equilibrate the solvent around the initial state
>> of the protein; if you don't, you'll get spurious forces that (if the
>> simulation doesn't immediately collapse) will lead to potentially
>> artificial structure changes.
>>
>> -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 | (410) 706-7441
>> http://mackerell.umaryland.edu/~jalemkul
>>
>> ================================================== -- Gromacs Users mailing
>> list
>>
>> * Please search the archive at
>> http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before
>> posting!
>>
>> * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists
>>
>> * For (un)subscribe requests visit
>> https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send
>> a mail to gmx-users-request at gromacs.org.

-- 
==================================================

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 | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==================================================