--- date: 2024-03-28 20:12 description: Fixing ADFRsuite on M1/MX chip Macs - CLI Tools tags: macOS, Cheminformatics, Tutorial --- # 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: * “python2.7” cannot be opened because the developer cannot be verified. * OpenBabel Error * Segmentation fault while running the [redocking tutorial](https://ccsb.scripps.edu/adcp/tutorial-redocking/) 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 ```bash /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: ```bash arch -x86_64 zsh ``` Now, we can install homebrew: ```bash /bin/bash -c "$(curl -fsSL https://raw.githubusercontent.com/Homebrew/install/HEAD/install.sh)" ``` Here is my output: ``` bash ➜ scrippstuff uname -a Darwin Navans-MacBook-Pro.local 23.3.0 Darwin Kernel Version 23.3.0: Wed Dec 20 21:31:00 PST 2023; root:xnu-10002.81.5~7/RELEASE_ARM64_T6020 x86_64 ➜ scrippstuff /bin/bash -c "$(curl -fsSL https://raw.githubusercontent.com/Homebrew/install/HEAD/install.sh)" ==> Checking for `sudo` 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. ```bash ➜ 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 openssl@3--3.2.1.sonoma.bottle.1.tar.gz 🍺 /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 `brew cleanup pyenv`... Disable this behaviour by setting HOMEBREW_NO_INSTALL_CLEANUP. Hide these hints with HOMEBREW_NO_ENV_HINTS (see `man brew`). ``` And, build the last version of Python 2.7 ```bash ➜ 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: ```bash ➜ 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 ADFRsuite_x86_64Darwin_1.0.tar.gz. Don't forget the `.` at the end ```bash ➜ 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: ```bash $ curl -o adfr.tar.gz https://ccsb.scripps.edu/adfr/download/1033/ ``` Uncompress it ```bash $ tar -xvzf adfr.tar.gz ``` Replace the provided Python archive with the one we created: ```bash $ 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` ```bash $ 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) ```bash $ 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` ```bash $ brew install cairo ``` ## Completing the re-docking tutorial ### Dowbloading the dataset ```bash $ curl -o tutorial-data.zip https://ccsb.scripps.edu/adcp/download/1063/ $ unzip tutorial-data.zip $ cd ADCP_tutorial_data/3Q47 ``` ### Conversion to PDBQT ```bash $ 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 ```bash $ 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 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 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 from ADFRcc.adfr import GridMap File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/__init__.py", line 34, in from ADFRcc.adfr import Parameters File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/adfr.py", line 43, in import ADFRcc.adfrcc as CPP File "/Users/navanchauhan/Developer/scrippstuff/ADFRsuite_x86_64Darwin_1.0/clean_install/CCSBpckgs/ADFRcc/adfrcc.py", line 28, in _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. ```bash $ 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: ```bash $ 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 ```bash $ 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.