gilsonlabucsd / apr

Attach-release-pull: A free energy calculation workflow

APR(attach-pull-release): a binding calculation approach

The current version of APR scripts (v1.1) is a demonstration of how to use the pulling approach to compute binding thermodynamics. You can apply it on most host-guest complexes with a minimal effort of setting up your system. If you are planning on computing the binding affinities for proteins, please be aware that careful adjustments of the protocols and scripts will be needed, based on the requirements of every particular system. In addition, be extremely cautious about using the APR approach to compute binding affinities for proteins with buried binding sites, as those may present convergence issues due to the significant conformational change of the protein during the pulling process. The APR tutorial for Amber users is available here: http://ambermd.org/tutorials/advanced/tutorial29/

The APR protocols have been used to generate moderate to strong correlations between experimental and computational binding thermodynamics based on a broad testing of host-guest systems including cucurbit[7]uril (CB7), octa acid (OA), tetra-endo-methyl octa-acid (TEMOA), α- and β-cyclodextrin (CD) with guest molecules. For the detailed theoretical framework, methodology, and validation of APR, please refer to the following publications:

Henriksen NM, Fenley AT, Gilson MK. Computational Calorimetry: High-Precision Calculation of Host-Guest Binding Thermodynamics. J. Chem. Theory Comput., 2015, 11(9), 4377-4394. http://pubs.acs.org/doi/abs/10.1021/acs.jctc.5b00405.

Yin J, Henriksen NM, Slochower DR, Gilson MK. The SAMPL5 Host-Guest Challenge: Computing Binding Free Energies and Enthalpies from Explicit Solvent Simulations by the Attach-Pull-Release (APR) Method. J. Comput. Aided Mol. Des., 2017, 31(1), 133-145. http://link.springer.com/article/10.1007/s10822-016-9970-8.

Velez-Vega C, Gilson MK. Overcoming Dissipation in the Calculation of Standard Binding Free Energies by Ligand Extraction. J. Comput. Chem., 2013, 34(27), 2360-2371. http://onlinelibrary.wiley.com/doi/10.1002/jcc.23398/full.

Fenley AT, Henriksen NM, Muddana HS, Gilson MK. Bridging Calorimetry and Simulation through Precise Calculations of Cucurbituril-Guest Binding Enthalpies. J. Chem. Theory Comput., 2014, 10(9), 4069-4078. http://pubs.acs.org/doi/abs/10.1021/ct5004109.

A recent advance of APR applications to protein-ligand binding can be found here: http://pubs.acs.org/doi/abs/10.1021/acs.jctc.7b00275.

apr's Issues

APR error

am tring to follow this tutorial http://ambermd.org/tutorials/advanced/tutorial29/APR_section1.html

I copied the directory apr.tar.gz
but python script failed with this error after running

python2 apr.py eq -i apr.in -s continue

Setting up the APR framework ...
Continue mode enabled. Checking previous simulations ...
pmemd.cuda is on.
Translational and rotational restraints will be imposed.
No conformational restraints applied.
Hydrogen mass repartitioning (HMR) is on.

You can use Ctrl+C to quit the program.

Traceback (most recent call last):
File "apr.py", line 1190, in
main()
File "apr.py", line 1165, in main
this.run_setup()
File "apr.py", line 893, in run_setup
tleap_in = open('windows/a00/tleap.in','r')
IOError: [Errno 2] No such file or directory: 'windows/a00/tleap.in'

I have amber2020 installed on my cluster but I also checked it with amber12 same error comes.

One more question:
Please tell me can I use this sampling method to study the ligand dissociation.

Thank you for your time in advance

Please guide me why the tleap script not copied in the windows files

Looking forward to hearing from you.

APR method to estimate binding free energy of ethanol to a kinase surface

Hi,
I wanted to know if you may provide some input files for the APR method used in bromodomain paper
Thanks

Error in the apr.py code

Hi,

By following the Amber tutorial (Computing Binding Free Energy using the Attach-Pull-Release (APR) Method ), I have been trying to use the APR code for simulating a host-guest system formed by a cisplatin molecule encapsulated into a carbon nanotube model. However, after the section 1, where one prepares the system and set up the restraints, the apr.py code located in section 2 did not work. I got the following error:

---

eduardo@inspiron5480:~/Documents/Projeto_Doutorado/cddp_CNH/3cddp_CNHox/US/APR$ python2.7 apr.py eq -i apr.in -s continue

---

Welcome to APR: a tool for binding calculations. Version 1.1
Written by:
Niel M. Henriksen, Jian (Jane) Yin, David R. Slochower
and the project leader:
Michael K. Gilson
Copyright (c) 2016-2017, University of California, San Diego

---

The current APR scripts may not be directly applied to protein systems, especially
for those with buried binding sites. Careful adjustments of the protocols and scripts
will be needed, based on the requirements of every particular system.

Checking the version of Python installed ...
You are using Python 2.7, which is perfect for running the APR scripts.

Setting up the APR framework ...
Continue mode enabled. Checking previous simulations ...
pmemd.cuda is on.
Translational and rotational restraints will be imposed.
No conformational restraints applied.
Hydrogen mass repartitioning (HMR) is on.

You can use Ctrl+C to quit the program.

Preparing folder windows/a00 2021-01-04 11:06:25 PM
Traceback (most recent call last):
File "apr.py", line 1190, in
main()
File "apr.py", line 1165, in main
this.run_setup()
File "apr.py", line 906, in run_setup
self.prepare_and_simulate('attachment')
File "apr.py", line 433, in prepare_and_simulate
shutil.copyfile('align_z.pdb', 'vac.pdb')
File "/usr/lib/python2.7/shutil.py", line 96, in copyfile
with open(src, 'rb') as fsrc:
IOError: [Errno 2] No such file or directory: 'align_z.pdb'
eduardo@inspiron5480:~/Documents/Projeto_Doutorado/cddp_CNH/3cddp_CNHox/US/APR$ ls

---

It is worthy to mention that I already have the align_z.pdb structure. Thus, I would like to ask you if you could help me in this error.

Sincerely,

Eduardo.

APR pull direction

Hello,
I am using APR script for cucurbiut[7]uryl and I love it:)

I have used it for ligands that are bigger (part of the ligand is outside of the host) and there is no doubt which direction should the script use as a pull direction. Now I have a case that ligand is inside and from a geometrical point of view, both directions of the pull are possible.

Question is, does it matters what pull direction I choose and I should perform both and the correct one is the one with lower energy?

The pull direction is not important, but why. It's because cucucubit[7]uryl is symmetrical (it has horizontal mirror plane). Or, it generally doesn't matter?

Thanks.

Adaptive pulling

Hi,
Thank you for providing the APR method and code. I'm wondering if the adaptive pulling mentioned in one of the reference paper is implemented in the APR (adaptive pulling meaning that the guest anchor atoms are not fixed and are assigned based on the fluctuations)? Thank you!
Best,
Lin

Error estimate test code

Will this line...

APR/test/test.py

Line 22 in 7236c24

sp.call('python2 apr.py analysis -i test.in > test.out', shell = True)

...run if there is no local copy of apr.py in the current directory? Perhaps it should be ../apr.py. As a separate issue, I'm not clear what issues will be caught by doing this testing. Is it to make sure that the free energy estimate is the same if we make changes to apr.py? If that's the case, then wouldn't the test suite have to copy over new restraints.dat files to reflect the change? I'm sure I'm misunderstanding the test scenario, so can you give an example?

APR prod stage problem

After finishing eq with no problem after "Fixed the manual_removal referenced before assignment bug", now I have problem in a prod stage. In the first window simulation start and mdinfo.01, mdout.01, traj.01 is produced. However the "SEM of the forces" is not checked. No info about it. And then all mdout.02, mdout.03, ..., mdout.20 are produced, of course almost empty. Also rst.01 is empty. Is it an Amber problem or in the APR.py script. Any help will be appreciated.

Thanks,
Maura

mdout.01.txt
mdout.02.txt
mdout.03.txt

rst.00.txt

Add the feature of solvating systems with organic solvent

Currently working on this feature.