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 =
= [1]
http://www.pas.rochester.edu/~yildirim/ =
-----------------------------------------------------------
On Thu, 24 Mar 2011, Mahmoud Soliman wrote:
Dear Thomas,
Actually your reply to Catherine has encouraged me to seek your advice about
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, [[2]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:
Dear Sir/Madam,
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
_______________________________________________
AMBER mailing list
[[3]2]AMBER.ambermd.org
[3][4]
http://lists.ambermd.org/mailman/listinfo/amber
Dr. Thomas Steinbrecher
formerly at the
BioMaps Institute
Rutgers University
610 Taylor Rd.
Piscataway, NJ 08854
_______________________________________________
AMBER mailing list
[[5]4]AMBER.ambermd.org
[5][6]
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
[6][7]
http://people.bath.ac.uk/mess20/
[7][8]
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:
[[9]8]mess20.bath.ac.uk
[[10]9]meelkot.zu.edu.eg
[[11]10]mahmoudelkot.gmail.com
References
1. [12]mailto:steinbrt.rci.rutgers.edu
2. [13]mailto:AMBER.ambermd.org
3. [14]
http://lists.ambermd.org/mailman/listinfo/amber
4. [15]mailto:AMBER.ambermd.org
5. [16]
http://lists.ambermd.org/mailman/listinfo/amber
6. [17]
http://people.bath.ac.uk/mess20/
7. [18]
http://www.bath.ac.uk/person/812559
8. [19]mailto:mess20.bath.ac.uk
9. [20]mailto:meelkot.zu.edu.eg
10. [21]mailto:mahmoudelkot.gmail.com
_______________________________________________
AMBER mailing list
[22]AMBER.ambermd.org
[23]
http://lists.ambermd.org/mailman/listinfo/amber
_______________________________________________
AMBER mailing list
[24]AMBER.ambermd.org
[25]
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
[26]
http://people.bath.ac.uk/mess20/
[27]
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:
[28]mess20.bath.ac.uk
[29]meelkot.zu.edu.eg
[30]mahmoudelkot.gmail.com
References
1.
http://www.pas.rochester.edu/~yildirim/
2. mailto:1]steinbrt.rci.rutgers.edu
3. mailto:2]AMBER.ambermd.org
4.
http://lists.ambermd.org/mailman/listinfo/amber
5. mailto:4]AMBER.ambermd.org
6.
http://lists.ambermd.org/mailman/listinfo/amber
7.
http://people.bath.ac.uk/mess20/
8.
http://www.bath.ac.uk/person/812559
9. mailto:8]mess20.bath.ac.uk
10. mailto:9]meelkot.zu.edu.eg
11. mailto:10]mahmoudelkot.gmail.com
12. mailto:steinbrt.rci.rutgers.edu
13. mailto:AMBER.ambermd.org
14.
http://lists.ambermd.org/mailman/listinfo/amber
15. mailto:AMBER.ambermd.org
16.
http://lists.ambermd.org/mailman/listinfo/amber
17.
http://people.bath.ac.uk/mess20/
18.
http://www.bath.ac.uk/person/812559
19. mailto:mess20.bath.ac.uk
20. mailto:meelkot.zu.edu.eg
21. mailto:mahmoudelkot.gmail.com
22. mailto:AMBER.ambermd.org
23.
http://lists.ambermd.org/mailman/listinfo/amber
24. mailto:AMBER.ambermd.org
25.
http://lists.ambermd.org/mailman/listinfo/amber
26.
http://people.bath.ac.uk/mess20/
27.
http://www.bath.ac.uk/person/812559
28. mailto:mess20.bath.ac.uk
29. mailto:meelkot.zu.edu.eg
30. mailto:mahmoudelkot.gmail.com
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Thu Mar 24 2011 - 11:00:02 PDT
