Critical Bug: Segmentation Fault in MutateResidue on PyRosetta M1 (ARM) Build

# Critical Bug: Segmentation Fault in MutateResidue on PyRosetta M1 (ARM) Build

## Summary

PyRosetta-4 2025.47 for M1 (ARM) crashes with segmentation fault (exit code 139) when performing core mutation operations required for any ddG-based protocol. The bug prevents all mutation-based workflows (Flex ddG, alanine scanning, saturation mutagenesis) from functioning on Apple Silicon hardware.

## Environment

```
Platform:        macOS (Apple Silicon M1/ARM64)
OS Version:      Darwin 25.1.0
PyRosetta:       PyRosetta-4 2025 [Rosetta PyRosetta4.Release.python310.m1 2025.47+release.8bb54e8a6dc3e1c027e4f028bdace6bd4691c823 2025-11-20T15:59:05]
Python:          3.10.19
Installation:    conda install -c https://conda.rosettacommons.org pyrosetta
Conda env:       miniconda base environment
```

## Bug Description

### Critical Failure Point

The segmentation fault occurs consistently in `MutateResidue().apply()`, which is the fundamental operation for all mutation-based protocols. The crash happens regardless of:

- Protein size (tested 12-157 residues)
- Mutation type (tested multiple residue types → Ala)
- Protocol complexity (fails even in minimal test case)
- Configuration parameters (fails with all settings)

### Operations Affected

All tested operations crash with exit code 139:

| Operation | Status | Location |
|-----------|--------|----------|
| `MutateResidue().apply()` | CRASH | Point mutation (CRITICAL) |
| `PackRotamersMover().apply()` | CRASH | Side-chain repacking |
| `MinMover().apply()` | CRASH | Energy minimization |
| `FastRelax().apply()` | CRASH | Structure relaxation |
| `pose_from_pdb()` | Works | Structure loading |
| `scorefxn(pose)` | Works | Energy calculation |

## Reproducible Test Case

### Minimal Example (12 residues)

```python
#!/usr/bin/env python3
"""
Minimal reproducible test for PyRosetta M1 bug.
Expected: Mutation applied successfully
Actual:   Segmentation fault (exit code 139)
"""

import pyrosetta
from pyrosetta.rosetta.protocols.simple_moves import MutateResidue

# Initialize PyRosetta
pyrosetta.init("-ignore_unrecognized_res -mute all")

# Load small test structure (12 residues)
pose = pyrosetta.pose_from_pdb("gamma.pdb")

print(f"Loaded: {pose.total_residue()} residues")
print("Attempting mutation R3A...")

# THIS CRASHES ON M1:
mutate = MutateResidue(target=3, new_res='A')
mutate.apply(pose)  # <-- SEGMENTATION FAULT

print("SUCCESS")  # Never reached
```

### Test Structures

| Structure | Size | PDB Source | Result |
|-----------|------|------------|--------|
| gamma.pdb | 12 residues | Simple test peptide | Segfault |
| model.pdb | 157 residues | eIF4E (AlphaFold) | Segfault |

Both structures are valid PDB files that load successfully with `pose_from_pdb()`.

### Stack Trace

```
PyRosetta inicializado
Função de energia: REF2015
Carregando estrutura: gamma.pdb
Estrutura carregada: 12 residues
Energia wild-type: 83.37 REU
Processando 9 mutações...
[1/9] R3A
[Exit code: 139]
```

No additional error messages or warnings are produced before the crash.

## Workarounds Attempted (All Failed)

### 1. Disable FastRelax → Use MinMover
**Result:** Segfault in MinMover

### 2. Disable All Minimization
**Result:** Segfault in PackRotamersMover

### 3. Disable Minimization + Repacking
**Result:** Segfault in MutateResidue

### 4. Minimalist Test (mutation + score only)
**Result:** Segfault in MutateResidue

### Conclusion
No workaround possible. The core `MutateResidue` operation is broken in the ARM build.

## Expected Behavior

The mutation should be applied to the pose without crashing:

```python
mutate = MutateResidue(target=3, new_res='A')
mutate.apply(pose)
print(f"Mutation successful: {pose.residue(3).name()}")  # Should print "ALA"
```

## Actual Behavior

```
[Exit code: 139]
Segmentation fault
```

The program crashes immediately during `mutate.apply(pose)` with no error message.

## Impact Assessment

### Unusable Features on M1

- ✗ Alanine scanning
- ✗ Flex ddG protocol
- ✗ Cartesian ddG protocol
- ✗ Point mutation analysis
- ✗ Saturation mutagenesis
- ✗ Protein design workflows
- ✗ Any protocol requiring `MutateResidue`
- ✗ Any protocol requiring minimization or repacking

### Usable Features on M1

- ✓ Structure loading (`pose_from_pdb`)
- ✓ Energy calculation (`scorefxn`)
- ✓ Basic pose operations (`clone`, `dump_pdb`)

## Root Cause Analysis

The segmentation fault likely originates from:

1. **Memory alignment issues** - ARM requires stricter memory alignment than x86
2. **SIMD instruction incompatibility** - x86 SSE/AVX vs ARM NEON
3. **Pointer arithmetic bugs** - Different pointer sizes or alignment assumptions
4. **Missing ARM-specific optimizations** - Code may assume x86 architecture

The bug appears to be in the compiled C++ binary, not in the Python interface layer, as:
- Python code executes correctly up to the C++ call
- No Python exceptions are raised
- The crash occurs during C++ pose manipulation

## Diagnostic Suggestions

For PyRosetta developers to debug this issue:

1. **Recompile with debugging tools:**
   ```bash
   # Add to compilation flags
   -fsanitize=address      # Detect memory errors
   -fsanitize=undefined    # Detect undefined behavior
   -g                      # Debug symbols
   -O0                     # Disable optimizations
   ```

2. **Check memory alignment:**
   ```cpp
   // Verify proper alignment for ARM
   static_assert(alignof(Pose) % 16 == 0);
   static_assert(alignof(Residue) % 16 == 0);
   ```

3. **Test SIMD code paths:**
   - Review all SIMD intrinsics for ARM compatibility
   - Consider using platform-agnostic SIMD libraries (e.g., xsimd, highway)

4. **Validate pointer operations:**
   - Check all pointer arithmetic in pose manipulation code
   - Verify no assumptions about pointer size or alignment

## Current Workarounds for Users

Since the M1 build is fundamentally broken for mutation workflows, users have three options:

### Option 1: Use Rosetta C++ (Recommended)

```bash
# Download from RosettaCommons
# https://www.rosettacommons.org/software/license-and-download

# Use native flex_ddg executable
$ROSETTA/main/source/bin/flex_ddg.macosclangrelease \
  -s input.pdb \
  -ddg:mut_file mutations.txt \
  -nstruct 50
```

**Advantages:** Stable, fast, full-featured, native ARM support

### Option 2: Use Intel x86 PyRosetta via Rosetta 2

```bash
# Install x86 PyRosetta (runs under Rosetta 2 emulation)
arch -x86_64 conda create -n pyrosetta_x86 python=3.10
arch -x86_64 conda activate pyrosetta_x86
arch -x86_64 conda install -c https://conda.rosettacommons.org pyrosetta
```

**Advantages:** Python interface maintained, more stable than ARM build
**Disadvantages:** Performance penalty from emulation

### Option 3: Use x86 Cloud Computing

- AWS EC2 (x86 instances)
- Google Cloud Compute
- Any Intel/AMD-based server

**Advantages:** Native x86 performance, scalable
**Disadvantages:** Requires cloud account, data transfer

## Testing Priority

For PyRosetta team testing:

1. **CRITICAL** - `MutateResidue` - Breaks all mutation workflows
2. **HIGH** - `PackRotamersMover` - Breaks repacking workflows
3. **HIGH** - `MinMover` - Breaks minimization workflows
4. **MEDIUM** - `FastRelax` - Alternative is MinMover (also broken)

## Additional Information

### PDB Test Files

I can provide the test PDB files used:
- `gamma.pdb` (12 residues) - minimal test case
- `model.pdb` (157 residues) - eIF4E structure

### Full Protocol Code

The complete Flex ddG protocol implementation is available if needed for testing. The code works correctly on Intel hardware and with Rosetta C++.

### Reproducibility

This bug is **100% reproducible** on:
- macOS M1 (ARM64)
- PyRosetta-4 2025.47
- Multiple protein structures
- Multiple mutation types

## System Information

```bash
# Architecture
uname -m
# arm64

# macOS Version
sw_vers
# ProductName:        macOS
# ProductVersion:     15.1
# BuildVersion:       24B83

# Python
python --version
# Python 3.10.19

# PyRosetta
python -c "import pyrosetta; print(pyrosetta.version())"
# PyRosetta-4 2025 [Rosetta PyRosetta4.Release.python310.m1 2025.47+release.8bb54e8a6dc3e1c027e4f028bdace6bd4691c823 2025-11-20T15:59:05]
```

## References

This bug was discovered while implementing protocols from:

1. Barlow KA, et al. (2018) **Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein–Protein Binding Affinity upon Mutation.** *J Phys Chem B.* 122(21):5389-5399. DOI: 10.1021/acs.jpcb.8b01639

2. Kellogg EH, et al. (2011) **Role of conformational sampling in computing mutation-induced changes in protein structure and stability.** *Proteins.* 79(3):830-8. DOI: 10.1002/prot.22921

3. Smith CA, Kortemme T (2008) **Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction.** *Structure.* 16(7):1126-33. DOI: 10.1016/j.str.2008.05.006

## Contact

**Reporter:** Madson Aragão
**Email:** madsondeluna@gmail.com
**Date:** 2024-12-04
**Issue Type:** Bug - Segmentation Fault
**Severity:** Critical (Core functionality broken on M1)

---

## Request for PyRosetta Team

Could you please:

1. Confirm if this is a known issue with the M1 build
2. Provide timeline for a fix if possible
3. Suggest any additional debugging steps I can perform
4. Confirm if the x86 build under Rosetta 2 is the recommended workaround until this is fixed

Thank you for your work on PyRosetta! Despite this M1 issue, the framework is excellent and works perfectly on Intel hardware.


Operation	Status	Location
`MutateResidue().apply()`	CRASH	Point mutation (CRITICAL)
`PackRotamersMover().apply()`	CRASH	Side-chain repacking
`MinMover().apply()`	CRASH	Energy minimization
`FastRelax().apply()`	CRASH	Structure relaxation
`pose_from_pdb()`	Works	Structure loading
`scorefxn(pose)`	Works	Energy calculation

Structure	Size	PDB Source	Result
gamma.pdb	12 residues	Simple test peptide	Segfault
model.pdb	157 residues	eIF4E (AlphaFold)	Segfault

Critical Bug: Segmentation Fault in MutateResidue on PyRosetta M1 (ARM) Build #8

Description

Critical Bug: Segmentation Fault in MutateResidue on PyRosetta M1 (ARM) Build

Summary

Environment

Bug Description

Critical Failure Point

Operations Affected

Reproducible Test Case

Minimal Example (12 residues)

Test Structures

Stack Trace

Workarounds Attempted (All Failed)

1. Disable FastRelax → Use MinMover

2. Disable All Minimization

3. Disable Minimization + Repacking

4. Minimalist Test (mutation + score only)

Conclusion

Expected Behavior

Actual Behavior

Impact Assessment

Unusable Features on M1

Usable Features on M1

Root Cause Analysis

Diagnostic Suggestions

Current Workarounds for Users

Option 1: Use Rosetta C++ (Recommended)

Option 2: Use Intel x86 PyRosetta via Rosetta 2

Option 3: Use x86 Cloud Computing

Testing Priority

Additional Information

PDB Test Files

Full Protocol Code

Reproducibility

System Information

References

Contact

Request for PyRosetta Team

Metadata

Metadata

Assignees

Labels

Type

Projects

Milestone

Relationships

Development

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