Installing PyRosetta (Mac)

Estimated setup time: 30–60 minutes

This guide walks you through installing everything you need to run computational protein science experiments on a Mac. Unlike Windows, Mac does not need WSL — you can work directly in the Mac Terminal.

Do I need to install Python? No. Miniconda (installed in Part 2) comes with its own Python. You do not need to install Python separately. If you already installed VSCode in the previous guide, you can skip Part 4 — just install the extra extensions listed there.

Not sure which chip your Mac has? Click the Apple menu () in the top-left corner, then click “About This Mac”. Look for “Chip” or “Processor”.

What you will learn

• How to set up a professional science computing environment on Mac
• How proteins are modelled using computational tools
• How mutations affect protein stability — key to drug resistance
• How to visualise and interpret scientific results

Software you will install

Part 1: Open the Terminal

Unlike Windows, Mac does not need WSL. You already have a built-in Linux-like terminal. All commands in this guide are typed into the Mac Terminal.

How to open Terminal

1. Press Command + Space to open Spotlight search
2. Type “Terminal”
3. Press Enter

You should see a window with a command prompt that looks something like: yourname@MacBook ~ %

Note: Keep the Terminal open throughout this entire guide. All commands below are typed here.

Check your Mac chip (important)

Run this command to confirm your chip type:

uname -m

• If it prints x86_64 — you have an Intel Mac. Follow all instructions normally.
• If it prints arm64 — you have an Apple Silicon Mac (M1/M2/M3/M4). Watch for the Apple Silicon warning boxes carefully.

Part 2: Install Miniconda

Miniconda manages Python and scientific packages. It keeps everything organised so different projects do not interfere with each other.

Intel Mac: Install Miniconda

# Download Miniconda for Intel Mac
curl -O https://repo.anaconda.com/miniconda/Miniconda3-latest-MacOSX-x86_64.sh

# Run the installer
bash Miniconda3-latest-MacOSX-x86_64.sh

Apple Silicon Mac (M1/M2/M3/M4): Install x86 Miniconda

Apple Silicon warning: PyRosetta does not yet run natively on Apple Silicon. You must install the x86_64 (Intel) version of Miniconda so Mac can emulate it using its built-in Rosetta 2. You must download the x86_64 version specifically — NOT the Apple Silicon version.

# Download the x86_64 version (NOT the Apple Silicon version)
curl -O https://repo.anaconda.com/miniconda/Miniconda3-latest-MacOSX-x86_64.sh

# Run installer using x86 emulation
arch -x86_64 bash Miniconda3-latest-MacOSX-x86_64.sh

Follow the installer prompts (all Mac users)

• Press ENTER to read the license agreement
• Hold SPACE to scroll through it quickly
• Type yes and press Enter to accept the license
• Press ENTER to confirm the default install location
• Type yes when asked to initialize Miniconda

Activate Miniconda

# Reload your terminal settings
source ~/.zshrc

# OR if that does not work, try:
source ~/.bash_profile

You should now see (base) at the start of your terminal prompt. This means Miniconda is active.

Apple Silicon: Verify x86 mode

file $(which python)
# Should show: Mach-O 64-bit executable x86_64
# If it shows arm64, the wrong version was installed

Part 3: Install PyRosetta

PyRosetta is the main protein modelling tool we will use. It is free for academic and educational use.

Step 1: Create a PyRosetta environment

# Intel Mac:
conda create -n pyrosetta python=3.8 -y

# Apple Silicon Mac — must force x86_64 architecture:
CONDA_SUBDIR=osx-64 conda create -n pyrosetta python=3.8 -y

Then activate the environment:

conda activate pyrosetta

You should now see (pyrosetta) at the start of your terminal prompt.

Step 2: Apple Silicon — lock environment to x86

Apple Silicon users only: Run this before installing PyRosetta to ensure all packages use the x86 version.

conda config --env --set subdir osx-64

Step 3: Install PyRosetta

# Install PyRosetta (works for both Intel and Apple Silicon)
conda install -c https://levinthal:paradox@conda.graylab.jhu.edu pyrosetta -y

Note: This download is large (about 1–2 GB). It may take 10–30 minutes. Be patient and do not close the terminal.

Step 4: Verify PyRosetta

python -c "import pyrosetta; pyrosetta.init(); print('PyRosetta works')"

If you see PyRosetta works printed, the installation was successful.

Apple Silicon: The very first time you run PyRosetta it may take 1–2 minutes to load. This is normal — it is being translated from x86 to ARM. Subsequent runs will be much faster.

Step 5: Install additional packages

# Install scientific Python packages
pip install pandas matplotlib notebook ipywidgets

# Install PyMOL for 3D visualisation
conda install -c conda-forge pymol-open-source -y

# Register PyRosetta as a Jupyter kernel
python -m ipykernel install --user --name pyrosetta --display-name "PyRosetta"

Part 4: Set up Visual Studio Code (VSCode)

Already installed VSCode? If you followed the previous guide and installed VSCode, skip Step 1. Just open VSCode and install the extensions in Step 2.

Step 1: Download VSCode

1. Go to https://code.visualstudio.com
2. Click the Download Mac Universal button
3. Open the downloaded .zip file — it will extract VSCode.app
4. Drag VSCode.app to your Applications folder
5. Open VSCode from your Applications folder or Launchpad

Mac security: If Mac says “VSCode cannot be opened because it is from an unidentified developer”, go to System Settings → Privacy & Security and click Open Anyway.

Step 2: Install required extensions

In VSCode, press Command+Shift+X to open Extensions and search for each of these:

Note: Mac does not need the WSL extension — that is Windows only.

Step 3: Point VSCode to your Conda Python

1. Press Command+Shift+P to open the command palette
2. Type “Python: Select Interpreter” and press Enter
3. Look for the option that contains pyrosetta in the path, e.g. ~/miniconda3/envs/pyrosetta/bin/python
4. Select it

Part 5: Set up your project folder

Step 1: Create the project folder

In Terminal (make sure you see (pyrosetta) at the start), run:

# Activate your PyRosetta environment
conda activate pyrosetta

# Create a folder for the project in your home directory
mkdir -p ~/drug_design_project

# Navigate to the folder
cd ~/drug_design_project

# Open VSCode in this folder
code .

Troubleshooting: If code . does not work, open VSCode manually, then go to File → Open Folder and select the drug_design_project folder.

Step 2: Create your notebook

1. In VSCode, press Command+Shift+P
2. Type “Create: New Jupyter Notebook” and press Enter
3. Press Command+Shift+S to save the file
4. Name it project1_stability.ipynb and click Save

Step 3: Select the PyRosetta kernel

1. Click Select Kernel in the top right corner of the notebook
2. Choose Jupyter Kernel
3. Select PyRosetta from the list

Troubleshooting: If PyRosetta does not appear in the list, open Terminal and run: python -m ipykernel install --user --name pyrosetta --display-name "PyRosetta" — then press Command+Shift+P in VSCode and type “Developer: Reload Window”.

Troubleshooting common problems

If you encounter an error not listed here, copy the error message and send it to your mentor at chensimichelle@gmail.com.