Conformer Ensemble Generation Via Crest

---
name: conformer-ensemble-generation-via-crest
description: Use when you have a molecular geometry (XYZ format) and need to explore
  its conformational space prior to quantum mechanical property calculation or when
  QCxMS2 workflow requires an ensemble of low-energy structures to enable systematic
  fragmentation pathways for EI mass spectrum simulation.
license: CC-BY-4.0
metadata:
  edam_operation: http://edamontology.org/operation_0360
  edam_topics:
  - http://edamontology.org/topic_3314
  - http://edamontology.org/topic_0176
  tools:
  - QCxMS2
  - xtb
  - CREST
  - ORCA
  - molbar
  - geodesic_interpolate
  - tblite
  techniques:
  - LC-MS
  license_tier: open
  provenance_tier: literature
derived_from:
- doi: 10.1021/jasms.5c00234
  title: QCxMS2
evidence_spans:
- Program package for the quantum mechanical calculation of EI mass spectra using
  automated reaction network exploration
- '**xtb** (version > 6.7.1 - bleeding edge version)'
- '**CREST** (version >= 3.0.2)'
- '**orca** (version >= 6.0.0)'
- '**molbar** (version >= 1.1.3)'
- '**geodesic_interpolate** (version'
claims: []
provenance:
  collection: https://w3id.org/holobiomicslab/asb-skill/collection/metabolomics/v2
  assembled_by: scripts/collect_metabolomics_collection.py
  sources:
  - build: coll_qcxms2_cq
    doi: 10.1021/jasms.5c00234
    title: QCxMS2
  dedup_kept_from: coll_qcxms2_cq
schema_version: 0.2.0
attribution:
  generator: AgenticScienceBuilder
  original_doi: 10.1021/jasms.5c00234
  all_source_dois:
  - 10.1021/jasms.5c00234
  zenodo_doi: 10.5281/zenodo.20794027
  curators: []
  promoter: Louis-Félix Nothias
  sponsor: CNRS & Université Côte d'Azur
---

# conformer-ensemble-generation-via-crest

## Summary

CREST (Conformer-Rotamer Ensemble Sampling Tool) automates the exploration of low-energy molecular chemical space by generating diverse conformational ensembles of input molecules. This skill is essential when automated reaction network exploration or fragmentation analysis requires sampling over multiple low-energy 3D structures.

## When to use

Apply this skill when you have a molecular geometry (XYZ format) and need to explore its conformational space prior to quantum mechanical property calculation or when QCxMS2 workflow requires an ensemble of low-energy structures to enable systematic fragmentation pathways for EI mass spectrum simulation.

## When NOT to use

- Input molecule is already a pre-optimized single conformation and conformational diversity is not relevant to the analysis goal.
- Computational resources are severely limited and sampling cost (OMP parallelization overhead) cannot be justified for the target application.
- Rigid or acyclic molecules with negligible conformational space (no rotatable bonds or stereoisomeric multiplicity).

## Inputs

- Molecular geometry file (XYZ or equivalent format)
- Conformer ensemble sampling parameters (energy thresholds, temperature, OMP thread count)

## Outputs

- Ensemble of low-energy conformer geometries (XYZ coordinates)
- Conformer cluster assignment and Boltzmann weights
- Energy-ranked conformer list

## How to apply

Initialize CREST (version ≥ 3.0.2) with a validated molecular geometry file and configure ensemble parameters. CREST functions as an OMP scheduler, dispatching efficient force-field and semiempirical quantum mechanical methods (such as xTB via integrated tblite or external xtb) to sample rotameric and conformeric minima. The tool performs automated low-energy structure discovery and cluster analysis, generating a Boltzmann-weighted ensemble of geometries. Aggregate the output ensemble and validate that structures span a reasonable energy range and represent distinct minima. The resulting ensemble is then used as input to downstream steps—either direct submission to higher-level QM packages (ORCA) or integration into reaction pathway interpolation (geodesic_interpolate) for fragmentation analysis.

## Related tools

- **xtb** (External semiempirical quantum mechanical engine for geometry optimization and conformer generation; required for QCG and some CREST functionalities despite integrated tblite in CREST ≥ 3.0.) — https://github.com/grimme-lab/xtb
- **tblite** (Integrated tight-binding library within CREST ≥ 3.0 for primary conformational sampling runtypes (replaces external xtb dependency for many workflows).)
- **QCxMS2** (Downstream tool that consumes CREST ensemble output to perform automated reaction network exploration and EI mass spectrum calculation.) — https://github.com/grimme-lab/QCxMS2
- **ORCA** (High-level quantum mechanical single-point energy and property calculator for ensemble members generated by CREST.)

## Evaluation signals

- Output ensemble contains multiple distinct conformer geometries with non-zero Boltzmann weights and energy separation consistent with expected rotameric or conformeric barriers.
- Cluster analysis produces stable, converged groups of similar structures with reproducible centroid energies across multiple runs.
- Ensemble covers energetically accessible conformational space (typically within 5–15 kcal/mol of global minimum for organic molecules) without excessive redundancy.
- All ensemble member geometries are valid (no clashes, reasonable bond/angle geometry) and optimizable by downstream QM packages without divergence.
- Log file reports completion without convergence warnings and documents OMP parallelization efficiency and sampling iterations.

## Limitations

- CREST sampling efficiency depends critically on correct installation and sourcing of xtb (version > 6.7.1 for bleeding-edge features); missing or mismatched versions will cause runtime errors or incomplete ensemble generation.
- Conformer enumeration may miss high-energy or kinetically trapped minima if sampling temperature or iteration limits are insufficient; careful parameter tuning is required for molecules with complex PES.
- Ensemble quality is sensitive to input geometry quality; malformed or severely non-optimized starting structures can seed poor conformer populations.
- Computational cost scales with molecular size and conformational complexity; very large or highly flexible molecules may require excessive wall-clock time or memory.

## Evidence

- [readme] CREST explores conformational space to generate ensemble: "CREST (abbreviated from ***C***onformer-***R***otamer ***E***nsemble ***S***ampling ***T***ool) is a program for the automated exploration of the low-energy molecular chemical space."
- [readme] CREST integrates xTB and tblite for sampling: "It functions as an OMP scheduler for calculations with efficient force-field and semiempirical quantum mechanical methods such as xTB, and provides a variety of capabilities for creation and analysis"
- [readme] CREST ≥3.0 embeds tblite, reducing xtb dependency: "While `xtb` is technically not needed for the primary runtypes of CREST versions >3.0 thanks to an integration of [`tblite`](https://github.com/tblite/tblite), some functionalities, like QCG, still"
- [other] CREST output feeds into QCxMS2 fragmentation workflow: "Run CREST (version >= 3.0.2) to explore conformational space and generate ensemble of low-energy structures."
- [readme] Version requirement for CREST in QCxMS2 pipeline: "**CREST** (version >= 3.0.2)"