Re: [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"  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

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

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==

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

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

==
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Re: [gmx-users] on non-equilibrium MD

[Brett]

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?


Brett











At 2016-04-03 01:08:19, "Justin Lemkul"  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
>
>jalem...@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
>
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>mail to gmx-users-requ...@gromacs.org.
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Re: [gmx-users] on non-equilibrium MD

[Brett]

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 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 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?

Brett










At 2016-04-02 10:21:33, "Justin Lemkul"  wrote:
>
>
>On 4/1/16 10:15 PM, Brett wrote:
>> Dear All,
>>
>> For non-equilibrium MD, does it mean there would be no need for the energy
>> minimization step, NVT equilibrium step and NPT equilibrium step before the
>> production MD? In which situation we use non-equilibrium MD, and in which
>> situation we use the production MD with energy minimization step, NVT
>> equilibrium step and NPT equilibrium step?
>>
>
>The term "non-equilibrium MD" covers a lot of different possibilities, each 
>with 
>their own applications - freezing, applying selective acceleration, pull code, 
>etc.  There is no single answer to when these should be applied because they 
>are 
>intrinsically different.
>
>Just because there is some perturbing or net force on the system does not mean 
>you can skip all the normal preparation steps.  I can practically guarantee 
>that 
>if you skip minimization and try to apply the pull code, your system will 
>immediately crash.  Some things are always necessary, but the exact protocol 
>depends on the goals at hand and the specific technique(s) being applied.
>
>-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
>
>jalem...@outerbanks.umaryland.edu | (410) 706-7441
>http://mackerell.umaryland.edu/~jalemkul
>
>==
>-- 
>Gromacs Users mailing list
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>* Please search the archive at 
>http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting!
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Re: [gmx-users] on non-equilibrium MD

[Justin Lemkul]

On 4/1/16 10:15 PM, Brett wrote:

Dear All,

For non-equilibrium MD, does it mean there would be no need for the energy
minimization step, NVT equilibrium step and NPT equilibrium step before the
production MD? In which situation we use non-equilibrium MD, and in which
situation we use the production MD with energy minimization step, NVT
equilibrium step and NPT equilibrium step?



The term "non-equilibrium MD" covers a lot of different possibilities, each with 
their own applications - freezing, applying selective acceleration, pull code, 
etc.  There is no single answer to when these should be applied because they are 
intrinsically different.


Just because there is some perturbing or net force on the system does not mean 
you can skip all the normal preparation steps.  I can practically guarantee that 
if you skip minimization and try to apply the pull code, your system will 
immediately crash.  Some things are always necessary, but the exact protocol 
depends on the goals at hand and the specific technique(s) being applied.


-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

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

==
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Gromacs Users mailing list

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[gmx-users] on non-equilibrium MD

[Brett]

Dear All,

For non-equilibrium MD, does it mean there would be no need for the energy 
minimization step, NVT equilibrium step and NPT equilibrium step before the 
production MD? In which situation we use non-equilibrium MD, and in which 
situation we use the production MD with energy minimization step, NVT 
equilibrium step and NPT equilibrium step?

Brett
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