Fixing ADFRSuite for Apple Silicon

We are going to be running everything through Rosetta 2. I am confident that if I had access to the original source code, I could find a way to run everything natively.

These are the following issues that we will be fixing in this part:

For the sake of simplicity, I am assuming that I am running all these commands in the folder ~/Developer/scrippstuff/

Installing Rosetta 2

We are going to run all of these steps in the terminal

/usr/sbin/softwareupdate --install-rosetta --agree-to-license

Install Homebrew for x86

Both versions of homebrew (x86 and arm64) can peacefully coexist on your system.

From now on, every command should be run in a terminal session that starts with this as the first command:

arch -x86_64 zsh

Now, we can install homebrew:

/bin/bash -c "$(curl -fsSL https://raw.githubusercontent.com/Homebrew/install/HEAD/install.sh)"

Here is my output:

  scrippstuff uname -a
Darwin Navans-MacBook-Pro.local 23.3.0 Darwin Kernel Version 23.3.0: Wed Dec 20 21:31:00 PST 2023; root:xnu-10002.81.5~7/RELEASE_ARM64_T6020 x86_64
➜  scrippstuff /bin/bash -c "$(curl -fsSL https://raw.githubusercontent.com/Homebrew/install/HEAD/install.sh)"
==> Checking for <!--CODE_BLOCK_1608--> access (which may request your password)...
Password:
==> This script will install:
/usr/local/bin/brew
/usr/local/share/doc/homebrew
/usr/local/share/man/man1/brew.1
/usr/local/share/zsh/site-functions/_brew
/usr/local/etc/bash_completion.d/brew
/usr/local/Homebrew
==> The following new directories will be created:
/usr/local/Cellar
/usr/local/Caskroom

Press RETURN/ENTER to continue or any other key to abort:
==> /usr/bin/sudo /bin/mkdir -p /usr/local/Cellar /usr/local/Caskroom
==> /usr/bin/sudo /bin/chmod ug=rwx /usr/local/Cellar /usr/local/Caskroom
==> /usr/bin/sudo /usr/sbin/chown navanchauhan /usr/local/Cellar /usr/local/Caskroom
==> /usr/bin/sudo /usr/bin/chgrp admin /usr/local/Cellar /usr/local/Caskroom
==> /usr/bin/sudo /usr/sbin/chown -R navanchauhan:admin /usr/local/Homebrew
==> /usr/bin/sudo /bin/mkdir -p /Users/navanchauhan/Library/Caches/Homebrew
==> /usr/bin/sudo /bin/chmod g+rwx /Users/navanchauhan/Library/Caches/Homebrew
==> /usr/bin/sudo /usr/sbin/chown -R navanchauhan /Users/navanchauhan/Library/Caches/Homebrew
==> Downloading and installing Homebrew...
remote: Enumerating objects: 47, done.
remote: Counting objects: 100% (47/47), done.
remote: Compressing objects: 100% (19/19), done.
remote: Total 47 (delta 28), reused 47 (delta 28), pack-reused 0
Unpacking objects: 100% (47/47), 6.11 KiB | 223.00 KiB/s, done.
From https://github.com/Homebrew/brew
 + 18ebdd8c8f...67a096fcbb tapioca-compiler-for-tty-rbi -> origin/tapioca-compiler-for-tty-rbi  (forced update)
Switched to and reset branch 'stable'
==> Updating Homebrew...
==> Installation successful!

==> Homebrew has enabled anonymous aggregate formulae and cask analytics.
Read the analytics documentation (and how to opt-out) here:
  https://docs.brew.sh/Analytics
No analytics data has been sent yet (nor will any be during this install run).

==> Homebrew is run entirely by unpaid volunteers. Please consider donating:
  https://github.com/Homebrew/brew#donations

==> Next steps:
- Run these two commands in your terminal to add Homebrew to your PATH:
    (echo; echo 'eval "$(/usr/local/bin/brew shellenv)"') >> /Users/navanchauhan/.zprofile
    eval "$(/usr/local/bin/brew shellenv)"
- Run brew help to get started
- Further documentation:
    https://docs.brew.sh

At this point, you don't need to edit your zshrc or zsh_profile.

Install pyenv

The reason we are installing pyenv is because it is easier to build Python 2.7.18 from scratch than messing around with codesigning and quarantine bs on macOS.

  scrippstuff brew install pyenv
==> Downloading https://ghcr.io/v2/homebrew/core/pyenv/manifests/2.3.36
############################################################################################################################################################### 100.0%
==> Fetching dependencies for pyenv: m4, autoconf, ca-certificates, openssl@3, pkg-config and readline
==> Downloading https://ghcr.io/v2/homebrew/core/m4/manifests/1.4.19
############################################################################################################################################################### 100.0%
==> Fetching m4
==> Downloading https://ghcr.io/v2/homebrew/core/m4/blobs/sha256:8434a67a4383836b2531a6180e068640c5b482ee6781b673d65712e4fc86ca76
############################################################################################################################################################### 100.0%
==> Downloading https://ghcr.io/v2/homebrew/core/autoconf/manifests/2.72
############################################################################################################################################################### 100.0%
==> Fetching autoconf
==> Downloading https://ghcr.io/v2/homebrew/core/autoconf/blobs/sha256:12368e33b89d221550ba9e261b0c6ece0b0e89250fb4c95169d09081e0ebb2dd
############################################################################################################################################################### 100.0%
==> Downloading https://ghcr.io/v2/homebrew/core/ca-certificates/manifests/2024-03-11
############################################################################################################################################################### 100.0%
==> Fetching ca-certificates
==> Downloading https://ghcr.io/v2/homebrew/core/ca-certificates/blobs/sha256:cab828953672906e00a8f25db751977b8dc4115f021f8dfe82b644ade03dacdb
############################################################################################################################################################### 100.0%
==> Downloading https://ghcr.io/v2/homebrew/core/openssl/3/manifests/3.2.1-1
############################################################################################################################################################### 100.0%
==> Fetching openssl@3
==> Downloading https://ghcr.io/v2/homebrew/core/openssl/3/blobs/sha256:ef8211c5115fc85f01261037f8fea76cc432b92b4fb23bc87bbf41e9198fcc0f
############################################################################################################################################################### 100.0%
==> Downloading https://ghcr.io/v2/homebrew/core/pkg-config/manifests/0.29.2_3
############################################################################################################################################################### 100.0%
==> Fetching pkg-config
==> Downloading https://ghcr.io/v2/homebrew/core/pkg-config/blobs/sha256:421571f340277c62c5cc6fd68737bd7c4e085de113452ea49b33bcd46509bb12
############################################################################################################################################################### 100.0%
==> Downloading https://ghcr.io/v2/homebrew/core/readline/manifests/8.2.10
############################################################################################################################################################### 100.0%
==> Fetching readline
==> Downloading https://ghcr.io/v2/homebrew/core/readline/blobs/sha256:9796e0ff1cc29ae7e75d8fc1a3e2c5e8ae2aeade8d9d59a16363306bf6c5b8f4
############################################################################################################################################################### 100.0%
==> Fetching pyenv
==> Downloading https://ghcr.io/v2/homebrew/core/pyenv/blobs/sha256:d117a99ed53502aff29109bfa366693ca623f2326e1e6b4db68fef7b7f63eeba
############################################################################################################################################################### 100.0%
==> Installing dependencies for pyenv: m4, autoconf, ca-certificates, openssl@3, pkg-config and readline
==> Installing pyenv dependency: m4
==> Downloading https://ghcr.io/v2/homebrew/core/m4/manifests/1.4.19
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/5b2a7f715487b7377e409e8ca58569040cd89f33859f691210c58d94410fd33b--m4-1.4.19.bottle_manifest.json
==> Pouring m4--1.4.19.sonoma.bottle.tar.gz
🍺  /usr/local/Cellar/m4/1.4.19: 13 files, 739.9KB
==> Installing pyenv dependency: autoconf
==> Downloading https://ghcr.io/v2/homebrew/core/autoconf/manifests/2.72
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/b73cdb320c4261bbf8d02d03e50dc755c869c5859c1d4e93616898fc7cd939ff--autoconf-2.72.bottle_manifest.json
==> Pouring autoconf--2.72.sonoma.bottle.tar.gz
🍺  /usr/local/Cellar/autoconf/2.72: 71 files, 3.6MB
==> Installing pyenv dependency: ca-certificates
==> Downloading https://ghcr.io/v2/homebrew/core/ca-certificates/manifests/2024-03-11
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/c431e0186df2ccc2ea942b34a3c26c2cebebec8e07ad6abdae48447a52c5f506--ca-certificates-2024-03-11.bottle_manifest.json
==> Pouring ca-certificates--2024-03-11.all.bottle.tar.gz
==> Regenerating CA certificate bundle from keychain, this may take a while...
🍺  /usr/local/Cellar/ca-certificates/2024-03-11: 3 files, 229.6KB
==> Installing pyenv dependency: openssl@3
==> Downloading https://ghcr.io/v2/homebrew/core/openssl/3/manifests/3.2.1-1
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/f7b6e249843882452d784a8cbc4e19231186230b9e485a2a284d5c1952a95ec2--openssl@3-3.2.1-1.bottle_manifest.json
==> Pouring [email protected]
🍺  /usr/local/Cellar/openssl@3/3.2.1: 6,874 files, 32.5MB
==> Installing pyenv dependency: pkg-config
==> Downloading https://ghcr.io/v2/homebrew/core/pkg-config/manifests/0.29.2_3
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/ac691fc7ab8ecffba32a837e7197101d271474a3a84cfddcc30c9fd6763ab3c6--pkg-config-0.29.2_3.bottle_manifest.json
==> Pouring pkg-config--0.29.2_3.sonoma.bottle.tar.gz
🍺  /usr/local/Cellar/pkg-config/0.29.2_3: 11 files, 656.4KB
==> Installing pyenv dependency: readline
==> Downloading https://ghcr.io/v2/homebrew/core/readline/manifests/8.2.10
Already downloaded: /Users/navanchauhan/Library/Caches/Homebrew/downloads/4ddd52803319828799f1932d4c7fa8d11c667049b20a56341c0c19246a1be93b--readline-8.2.10.bottle_manifest.json
==> Pouring readline--8.2.10.sonoma.bottle.tar.gz
🍺  /usr/local/Cellar/readline/8.2.10: 50 files, 1.7MB
==> Installing pyenv
==> Pouring pyenv--2.3.36.sonoma.bottle.tar.gz
🍺  /usr/local/Cellar/pyenv/2.3.36: 1,158 files, 3.4MB
==> Running <!--CODE_BLOCK_1611-->...
Disable this behaviour by setting HOMEBREW_NO_INSTALL_CLEANUP.
Hide these hints with HOMEBREW_NO_ENV_HINTS (see <!--CODE_BLOCK_1612-->).

And, build the last version of Python 2.7

  scrippstuff PYENV_ROOT="~/Developer/scrippstuff" pyenv install 2.7.18
python-build: use openssl from homebrew
python-build: use readline from homebrew
Downloading Python-2.7.18.tar.xz...
-> https://www.python.org/ftp/python/2.7.18/Python-2.7.18.tar.xz
Installing Python-2.7.18...
patching file configure
patching file configure.ac
patching file setup.py
patching file 'Mac/Tools/pythonw.c'
patching file setup.py
patching file 'Doc/library/ctypes.rst'
patching file 'Lib/test/test_str.py'
patching file 'Lib/test/test_unicode.py'
patching file 'Modules/_ctypes/_ctypes.c'
patching file 'Modules/_ctypes/callproc.c'
patching file 'Modules/_ctypes/ctypes.h'
patching file 'Modules/_ctypes/callproc.c'
patching file setup.py
patching file 'Mac/Modules/qt/setup.py'
patching file setup.py
python-build: use readline from homebrew
python-build: use zlib from xcode sdk
Installed Python-2.7.18 to /Users/navanchauhan/Developer/scrippstuff/~/Developer/scrippstuff/versions/2.7.18

Test the new installation:

  scrippstuff ~/Developer/scrippstuff/\~/Developer/scrippstuff/versions/2.7.18/bin/python2.7
Python 2.7.18 (default, Mar 28 2024, 20:47:13)
[GCC Apple LLVM 15.0.0 (clang-1500.1.0.2.5)] on darwin
Type "help", "copyright", "credits" or "license" for more information.
>>> from random import randint
>>> randint(0,10)
6
>>> exit()

Now, we can compress this newly created Python version into a tar.gz file to replace the one provided in ADFRsuitex8664Darwin_1.0.tar.gz. Don't forget the . at the end

  scrippstuff tar -C ./\~/Developer/scrippstuff/versions/2.7.18 -czf new.tar.gz .

Install ADFRsuite

If you don't already have the tarball, you can download it by:

$ curl -o adfr.tar.gz https://ccsb.scripps.edu/adfr/download/1033/

Uncompress it

$ tar -xvzf adfr.tar.gz

Replace the provided Python archive with the one we created:

$ cd ADFRsuite_x86_64Darwin_1.0
$ mv new.tar.gz Python2.7.tar.gz

Note: For some reason simply copying it doesn't work and you need to use mv

Just to not mess with anything else, I will be installing everything in a folder called clean_install

$ mkdir clean_install
$ ./install.sh -d clean_install
...
 ADFRsuite installation complete.
To run agfr, agfrgui, adfr, autosite, about, pythonsh scripts located at:
/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/bin
add  /Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/bin to the path environment variable in .cshrc or .bashrc:
.cshrc:
set path = (/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/bin $path)

.bashrc:
export PATH=/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/bin:$PATH

Now, to test agfr, first run the command (replacing navanchauhan with yout username)

$ export PATH=/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/bin:$PATH
$ agfr
➜  ADFRsuite_x86_64Darwin_1.0 agfr
==============================
*** Open Babel Error  in openLib
  /Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/lib/openbabel/2.4.1/acesformat.so did not load properly.
 Error: dlopen(/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/lib/openbabel/2.4.1/acesformat.so, 0x0009): Library not loaded: /opt/X11/lib/libcairo.2.dylib
  Referenced from: <24174F3E-2670-79AC-4F26-F8B49774194A> /Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/lib/openbabel/2.4.1/acesformat.so
  Reason: tried: '/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/lib/libcairo.2.dylib' (no such file), '/opt/X11/lib/libcairo.2.dylib' (no such file), '/System/Volumes/Preboot/Cryptexes/OS/opt/X11/lib/libcairo.2.dylib' (no such file), '/opt/X11/lib/libcairo.2.dylib' (no such file), '/usr/local/lib/libcairo.2.dylib' (no such file), '/usr/lib/libcairo.2.dylib' (no such file, not in dyld cache)
==============================

Fixing Open Babel Error

$ brew install cairo

Completing the re-docking tutorial

Dowbloading the dataset

$ curl -o tutorial-data.zip https://ccsb.scripps.edu/adcp/download/1063/
$ unzip tutorial-data.zip
$ cd ADCP_tutorial_data/3Q47

Conversion to PDBQT

$ reduce 3Q47_rec.pdb > 3Q47_recH.pdb
$ reduce 3Q47_pep.pdb > 3Q47_pepH.pdb

Preparing Receptor

$ prepare_receptor -r 3Q47_recH.pdb
$ prepare_ligand -l 3Q47_pepH.pdb

Generate Target File

$ agfr -r 3Q47_recH.pdbqt -l 3Q47_pepH.pdbqt -asv 1.1 -o 3Q47
➜  3Q47 agfr -r 3Q47_recH.pdbqt -l 3Q47_pepH.pdbqt -asv 1.1 -o 3Q47
Traceback (most recent call last):
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFR/bin/runAGFR.py", line 36, in <module>
    from ADFR.utils.runAGFR import runAGFR
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFR/utils/runAGFR.py", line 41, in <module>
    from ADFR.utils.maps import flexResStr2flexRes
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFR/utils/maps.py", line 35, in <module>
    from ADFRcc.adfr import GridMap
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/__init__.py", line 34, in <module>
    from ADFRcc.adfr import Parameters
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/adfr.py", line 43, in <module>
    import ADFRcc.adfrcc as CPP
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/adfrcc.py", line 28, in <module>
    _adfrcc = swig_import_helper()
  File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/adfrcc.py", line 24, in swig_import_helper
    _mod = imp.load_module('_adfrcc', fp, pathname, description)
ImportError: dlopen(/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/_adfrcc.so, 0x0002): Library not loaded: /Users/Shared/mgltoolsDev/src/homebrew/opt/gcc/lib/gcc/8/libgomp.1.dylib
  Referenced from: <424BF61E-BF0F-351E-B546-E82EBBD8FBF5> /Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/_adfrcc.so
  Reason: tried: '/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/lib/libgomp.1.dylib' (no such file), '/Users/Shared/mgltoolsDev/src/homebrew/opt/gcc/lib/gcc/8/libgomp.1.dylib' (no such file), '/System/Volumes/Preboot/Cryptexes/OS/Users/Shared/mgltoolsDev/src/homebrew/opt/gcc/lib/gcc/8/libgomp.1.dylib' (no such file), '/Users/Shared/mgltoolsDev/src/homebrew/opt/gcc/lib/gcc/8/libgomp.1.dylib' (no such file), '/usr/local/lib/libgomp.1.dylib' (no such file), '/usr/lib/libgomp.1.dylib' (no such file, not in dyld cache)  3Q47

Sometimes this error is simply outputted as a segmentation fault. But, it is because it cannot find the libgomp.1.dylib. I haven't tested using a newer version of GCC to make it work. Building GCC 8 yourself is absolutely painful. We are going to use a copy generated by the homebrew team.

$ cd ../../
$ pwd
/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0
$ curl -L -H "Authorization: Bearer QQ==" -o gcc8amd64.tar.gz https://ghcr.io/v2/homebrew/core/gcc/8/blobs/sha256:438d5902e5f21a5e8acb5920f1f5684ecfe0c645247d46c8d44c2bbe435966b2
$ tar -xzf gcc8amd64.tar.gz
$ cp -r gcc@8/8.5.0/lib/gcc/8/* clean_install/lib/

Now, we should be able to go back and run the target generation command:

$ cd ADCP_tutorial_data/3Q47
$ agfr -r 3Q47_recH.pdbqt -l 3Q47_pepH.pdbqt -asv 1.1 -o 3Q47
#################################################################
# If you used AGFR in your work, please cite:                   #
#                                                               #
# P.A. Ravindranath S. Forli, D.S. Goodsell, A.J. Olson and     #
# M.F. Sanner                                                   #
# AutoDockFR: Advances in Protein-Ligand Docking with           #
...

Docking Peptide

$ adcp -t 3Q47.trg -s npisdvd -N 20 -n 1000000 -o 3Q47_redocking -ref 3Q47_pepH.pdb

There you have it. Running ADCP on the newest macOS version against all odds.

I haven't yet looked into fixing/patching agfrgui as I don't use the software. But, if someone reallllly needs to run it on Apple Silicon, I am happy to take a look at monkeypatching it.

In case years down the line the prebuilt version of GCC 8 is not available, let me know so I can replace the link with my mirror.

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