# Re: [AMBER] How to get the free energy landscape from a MD simulation?

From: Mahmoud Soliman <mahmoudelkot.gmail.com>
Date: Thu, 24 Mar 2011 21:08:30 +0200

Thanks Ilyas for your patience and support! much appreciated!
Best wishes
Mahmoud
On 3/24/11 8:33 PM, Ilyas Yildirim wrote:

Mahmoud - It seems that there is no tutorial for umbrella sampling/WHAM
approach in [1]http://ambermd.org/tutorials , but you can check out the
following website for an example, which uses AMBER and WHAM to calculate
the PMF for butane.
[2]http://projects.eml.org/mcm/people/wang/PMF/tutorial.html
You should also get familiar with Alan Grossfield's WHAM in order to get
the free energy surface:
[3]http://membrane.urmc.rochester.edu/sites/default/files/wham/doc/doc.pdf
This example is for one torsional angle, but you can extend this
methodology to any case you want. The basic approach is to use NMR
restraints (distance/angle/torsion, etc.) to put bias to the potential
energy on a reaction coordinate, and then use weighted histogram analysis
to predict the PMF curve. The reaction coordinate can be anything. This
example is a 1D PMF example, and it is possible to do 2D PMF calculations
with AMBER. Note that in AMBER10/11, you can use generalized coordinates,
which I think is very useful to combine with umbrella sampling.
For the targetted MD/WHAM approach, check out the following papers. Even
though it does not use NMR restraints, the basics are the same.
Noy et al., Theoretical study of large conformational transitions in DNA:
B <-> A conformational change in water and ethanol/water, NAR 35,
3330-3338, 2007.
Banavali and Roux, Free energy landscape of A-DNA to B-DNA conversion in
aqueous solution, JACS 127, 6866-6876, 2005.
Note also that in these approaches/calculations (in the example and above
papers), you cannot have any reaction that will change the covalent
bonding of the system. Maybe you can do QMMM umbrella sampling-WHAM for
that purpose but I am not familiar with that. People in this mailing list
might comment on that.
Best regards,
Ilyas Yildirim, Ph.D.
-----------------------------------------------------------
= Department of Chemistry - 2145 Sheridan Road =
= Northwestern University - Evanston, IL 60208 =
= Ryan Hall #4035 (Nano Building) - Ph.: (847)467-4986 =
= [4]http://www.pas.rochester.edu/~yildirim/ =
-----------------------------------------------------------
On Thu, 24 Mar 2011, Mahmoud Soliman wrote:

Dear Ilyas,
Thanks so much for your email, it is actually comprehensive!
In principle, I would like to explore the free energy profile for
nucleophilic substitution reaction happens between Glu residue (Nu) and an
elctrophilic carbon atom in the substrate - I start from non
covalent intermediate and end up with a covalently bonded intermediate, so
that I have to use QM/MM approach. I have had difficulty (but eventually
succeeded ) to publish a proton transfer reaction for
the same complex but using AM1/OPLS PMF/WHAM (using Dynamo software) and
the main criticism I got is the AM1 level of theory. To this end, I
decided to try Amber since I can use DFTB description for the
QM part....Anyway that was my story.
I think my study belongs to your second proposal (below)
As I mentioned I am new to such calculations in Amber , can you forward me
to some tutorial or some examples on how to set up such calculations with
Amber 10? I have set up my system (Minimized and
equilibrated), that would be appreciated!
Best wishes
Mahmoud
On 3/24/11 6:25 PM, Ilyas Yildirim wrote:
As Dave, Adrian, and Thomas pointed out, you can use umbrella sampling and
combine it with WHAM to get a free energy profile for a transformation.
Here are my thoughts on free energy calculations that you can do with
AMBER:
1. If your system needs to do alchemical transformations such as change in
charge, atom type, etc, you need to use thermodynamic integration (TI).
But if there is conformational change in the alchemical transformation, TI
will not work.
2. If there is a conformational change that you want to analyze, you can
use umbrella sampling. The important thing in umbrella sampling is to find
a good reaction coordinate to mimic the transformation. In AMBER9, you can
use distance, angular, and torsional restraints for the reaction
coordinate, but in AMBER10 and 11, you can use generalized distance,
angular, and torsional restraints (such as the center of geometries of the
groups), which I think are very useful. You can also combine targetted MD
with WHAM to get a free energy surface. I think Benoit Roux as well as
Orozco's group did work on tMD/WHAM approach. All these assume that you
are interested on equilibrium dynamics.
3. The other option is to run a very long MD simulation, and analyze the
results, such as histogram analysis as Thomas pointed out. But what is a
long MD simulation? 1 ns, 1 micros, 1 millis? If you have a big system, I
do not think that this approach will work. If you have a small system such
as a monomer system, then this approach can be used to see conformational
transformations. We published a paper, which uses this methodology, to
predict the deltaG for mononucleosides, but I do not think that it will
work on bigger systems.
At the end, the computational predictions should be compared to
experimental measurements. All these calculations use force fields, which
are parameters/numbers given to the program so that you can mirror the
real nature/environment. If your system has nucleic acids in it such as
DNA/RNA/LNA or any other version, and if the property you are looking for
is something very unique, the force field might not be able predict the
experimental results. Thus, use the latest force field for your system in
doing any of the above calculations.
All the best,
Ilyas Yildirim, Ph.D.
-----------------------------------------------------------
= Department of Chemistry - 2145 Sheridan Road =
= Northwestern University - Evanston, IL 60208 =
= Ryan Hall #4035 (Nano Building) - Ph.: (847)467-4986 =
= [5]http://www.pas.rochester.edu/~yildirim/ =
-----------------------------------------------------------
On Thu, 24 Mar 2011, Mahmoud Soliman wrote:
Dear Thomas,
my case: I need to do a PMF for some reaction coordinate (nucleophilic
attack) using QM/MM facility in Amber 10. I read through steered MD
simulation but it sounds to me (from the comments I get from Amber
users/developers) that SMD is a bit doggy and some people getting some
trouble to publish work with SMD. Is there any EASY and reliable
alternative
in Amber 10 that I can apply to do a PMF for NU or PT reactions in
enzyme???
do you have any tutorial/example for the methode you explain below to
Catherine that I can use??
Best wishes
Mahmoud
On 3/24/11 5:04 PM, [[6]1]steinbrt.rci.rutgers.edu wrote:
Hi,
I am not sure if this is what you mean, but if you can define a clear
reaction coordinate x for the change you see, e.g. some distance, you can
use ptraj to analyse the time series of movement along it, compute a
histogram P(x) and transform it into a potential of mean force via dF=
-RTln P(x). This is only meaningful if all points along x are well sampled
though.
Kind Regards,
Thomas
On Thu, March 24, 2011 10:55 am, Catein Catherine wrote:
I have done the MD simulations. I would like to analysis the free energy
landscapes of a conformational change during a long MD simulations.
Can I do it with ptraj or any other softwares or scripts?
Best regards,
Catherine
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Dr. Thomas Steinbrecher
formerly at the
BioMaps Institute
Rutgers University
610 Taylor Rd.
Piscataway, NJ 08854
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--
*************************************************
Mahmoud E. Soliman
Computational Chemistry & Modeling (PhD)
Department of Chemistry
University of Bath
Bath
BA2 7AY
United Kingdom
[6][11]http://people.bath.ac.uk/mess20/
[7][12]http://www.bath.ac.uk/person/812559
*********************************************
Mahmoud E. Soliman
Lecturer of pharmaceutical organic chemistry
Pharmaceutical Organic Chemistry Dept.
Faculty of pharmacy
Zagazig University
Zagazig
Egypt
**********************************************
Email:
[[13]8]mess20.bath.ac.uk
[[14]9]meelkot.zu.edu.eg
[[15]10]mahmoudelkot.gmail.com
References
1. [16]mailto:steinbrt.rci.rutgers.edu
2. [17]mailto:AMBER.ambermd.org
3. [18]http://lists.ambermd.org/mailman/listinfo/amber
4. [19]mailto:AMBER.ambermd.org
5. [20]http://lists.ambermd.org/mailman/listinfo/amber
6. [21]http://people.bath.ac.uk/mess20/
7. [22]http://www.bath.ac.uk/person/812559
8. [23]mailto:mess20.bath.ac.uk
9. [24]mailto:meelkot.zu.edu.eg
10. [25]mailto:mahmoudelkot.gmail.com
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AMBER mailing list
[26]AMBER.ambermd.org
[27]http://lists.ambermd.org/mailman/listinfo/amber
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AMBER mailing list
[28]AMBER.ambermd.org
[29]http://lists.ambermd.org/mailman/listinfo/amber
--
*************************************************
Mahmoud E. Soliman
Computational Chemistry & Modeling (PhD)
Department of Chemistry
University of Bath
Bath
BA2 7AY
United Kingdom
[30]http://people.bath.ac.uk/mess20/
[31]http://www.bath.ac.uk/person/812559

*********************************************
Mahmoud E. Soliman
Lecturer of pharmaceutical organic chemistry
Pharmaceutical Organic Chemistry Dept.
Faculty of pharmacy
Zagazig University
Zagazig
Egypt
**********************************************
Email:
[32]mess20.bath.ac.uk
[33]meelkot.zu.edu.eg
[34]mahmoudelkot.gmail.com

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AMBER mailing list
[35]AMBER.ambermd.org
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--

*************************************************

Mahmoud E. Soliman

Computational Chemistry & Modeling (PhD)

Department of Chemistry

University of Bath

Bath

BA2 7AY

United Kingdom

[37]http://people.bath.ac.uk/mess20/

[38]http://www.bath.ac.uk/person/812559

*********************************************

Mahmoud E. Soliman

Lecturer of pharmaceutical organic chemistry

Pharmaceutical Organic Chemistry Dept.

Faculty of pharmacy

Zagazig University

Zagazig

Egypt

**********************************************

Email:

[39]mess20.bath.ac.uk

[40]meelkot.zu.edu.eg

[41]mahmoudelkot.gmail.com

References

1. http://ambermd.org/tutorials
2. http://projects.eml.org/mcm/people/wang/PMF/tutorial.html
3. http://membrane.urmc.rochester.edu/sites/default/files/wham/doc/doc.pdf
4. http://www.pas.rochester.edu/~yildirim/
5. http://www.pas.rochester.edu/~yildirim/
6. mailto:1]steinbrt.rci.rutgers.edu
7. mailto:2]AMBER.ambermd.org
8. http://lists.ambermd.org/mailman/listinfo/amber
9. mailto:4]AMBER.ambermd.org
10. http://lists.ambermd.org/mailman/listinfo/amber
11. http://people.bath.ac.uk/mess20/
12. http://www.bath.ac.uk/person/812559
13. mailto:8]mess20.bath.ac.uk
14. mailto:9]meelkot.zu.edu.eg
15. mailto:10]mahmoudelkot.gmail.com
16. mailto:steinbrt.rci.rutgers.edu
17. mailto:AMBER.ambermd.org
18. http://lists.ambermd.org/mailman/listinfo/amber
19. mailto:AMBER.ambermd.org
20. http://lists.ambermd.org/mailman/listinfo/amber
21. http://people.bath.ac.uk/mess20/
22. http://www.bath.ac.uk/person/812559
23. mailto:mess20.bath.ac.uk
24. mailto:meelkot.zu.edu.eg
25. mailto:mahmoudelkot.gmail.com
26. mailto:AMBER.ambermd.org
27. http://lists.ambermd.org/mailman/listinfo/amber
28. mailto:AMBER.ambermd.org
29. http://lists.ambermd.org/mailman/listinfo/amber
30. http://people.bath.ac.uk/mess20/
31. http://www.bath.ac.uk/person/812559
32. mailto:mess20.bath.ac.uk
33. mailto:meelkot.zu.edu.eg
34. mailto:mahmoudelkot.gmail.com
35. mailto:AMBER.ambermd.org
36. http://lists.ambermd.org/mailman/listinfo/amber
37. http://people.bath.ac.uk/mess20/
38. http://www.bath.ac.uk/person/812559
39. mailto:mess20.bath.ac.uk
40. mailto:meelkot.zu.edu.eg
41. mailto:mahmoudelkot.gmail.com
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Received on Thu Mar 24 2011 - 12:30:02 PDT
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