Molecular Conformer Search & Ranking

Goal

Generate a diverse ensemble of low-energy conformers for a given molecule. The workflow combines:

1. Stochastic sampling using RDKit's ETKDG algorithm (Experimental Torsion Distance Geometry).
2. High-accuracy relaxation using Machine Learning Interatomic Potentials (MLIPs) to get near-DFT quality geometries and energies.
3. Deduplication and Boltzmann weighting to identify the most relevant conformers at finite temperature.

[!IMPORTANT] This skill is optimized for organic molecules and uses MACE-OFF23 models by default. For inorganic clusters, switch to MACE-OMAT or MatGL models.

Recommended Models

• MACE-OFF23: MACE-OFF23-small (default), MACE-OFF23-medium — trained on organic molecules (Env: mace-agent)
• MACE-MH: MACE-MH-1 with head omol — multi-head model with molecular head (Env: mace-agent)
• UMA: uma-s-1p1 with head omol — general molecular model (Env: fairchem-agent)

1. Prerequisites

• Conda Environment: mace-agent (recommended as it includes both mace and rdkit).
• Input: SMILES string or a structure file (.xyz, .sdf, .mol2, .pdb).

2. Methodology

1. Generation: Generate N initial conformers using RDKit's EmbedMultipleConfs with ETKDGv3.
2. Relaxation: Optimize the geometry of each conformer using the selected MLIP (fmax = 0.01 eV/Å).
3. Deduplication/Clustering: Filter redundant conformers by simple RMSD thresholding (default), Hierarchical clustering, or K-Means clustering. Only the lowest-energy conformer in each cluster is kept.
4. Ranking: Sort unique conformers by energy.
5. Boltzmann Weighting: Calculate population probability $P_i$ at temperature $T$: $$P_i = \frac{e^{-(E_i - E_{min}) / k_B T}}{\sum_j e^{-(E_j - E_{min}) / k_B T}}$$

3. Usage

Basic Usage (SMILES)

Generate 30 conformers for a molecule (e.g., aspirin) and relax with MACE-OFF23:

# Env: mace-agent
python .agents/skills/chem-conformer-search/scripts/conformer_search.py \
    --smiles "CC(=O)Oc1ccccc1C(=O)O" \
    --num_conformers 30 \
    --output_dir research/aspirin_conformers

Advanced Usage (Structure File + Options)

# Env: mace-agent
python .agents/skills/chem-conformer-search/scripts/conformer_search.py \
    --structure my_molecule.sdf \
    --num_conformers 100 \
    --rms_threshold 0.5 \
    --dedup_threshold 0.1 \
    --temperature 298.15 \
    --model_type mace \
    --model_name MACE-OFF23-small \
    --device cuda \
    --output_dir research/my_molecule_search

Key Parameters

Argument	Default	Description
--smiles	-	SMILES string of the molecule
--structure	-	Path to input structure file (alternative to SMILES)
--num_conformers	50	Number of initial conformers to generate with RDKit
--rms_threshold	0.2	RDKit pruning threshold (Å) to discard similar initial conformers
--clustering	rmsd	Method to filter conformers: rmsd, hierarchical, or kmeans
--dedup_threshold	0.1	Post-relaxation RMSD threshold (Å) to merge identical conformers or cut for hierarchical
--num_clusters	5	Number of clusters if --clustering kmeans is used
--energy_threshold	0.5	Max energy above global minimum (eV) to keep before RMSD comparison. Set to 0 to disable
--fmax	0.01	Force convergence criterion for relaxation (eV/Å)
--temperature	298.15	Temperature (K) for Boltzmann weighting
--model_type	mace	MLIP backend (mace, matgl, fairchem)
--model_name	MACE-OFF23-small	Specific model checkpoint to use

4. Output Files

The output directory will contain:

1. conformer_results.json: A summary file containing:
   • List of unique conformers with their energies, relative energies, and Boltzmann weights.
   • Paths to the corresponding XYZ files.
   • Metadata (model used, parameters).
2. conf_000.xyz, conf_001.xyz, ...: The relaxed structures of the unique conformers, sorted by energy (000 is the global minimum found).

5. Examples

See examples/aspirin for a complete example run on Acetylsalicylic acid.

6. Constraints

• Environment: Use the conda environment matching the chosen model: mace-agent (MACE), fairchem-agent (FairChem/UMA), or matgl-agent (MatGL). All include RDKit.
• Input: Either --smiles or --structure must be provided, but not both.
• Molecule Type: Optimized for organic molecules. For inorganic clusters, switch to MACE-OMAT or MatGL models.
• Non-periodic: All conformers are treated as non-periodic (isolated molecules).

7. References

• Riniker, S.; Landrum, G. A., "Better Informed Distance Geometry: Using What We Know To Improve Conformation Generation", J. Chem. Inf. Model., 2015, 55, 2562. DOI

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Author: Bowen Deng Contact: GitHub @learningmatter-mit