Alchemical Approaches in Molecular Design

Alchemical approaches harness non‐physical transformations of atomic nuclei and electrons to predict molecular properties and guide design without exhaustive enumeration. By treating changes in nuclear charge as a perturbation, researchers employ Taylor-series expansions or density derivatives to estimate energies, structures and response functions of target systems from a single reference calculation. This paradigm accelerates exploration of chemical compound space, enabling rapid scans of alloy compositions, catalyst surfaces and drug‐like scaffolds. Coupling alchemical perturbation theory with automatic differentiation and machine-learning frameworks has further enhanced predictive accuracy and enabled end-to-end optimisation of basis sets and molecular geometries. Practical applications range from semiconductor alloy discovery to catalyst screening and drug lead optimisation, all achieved at a fraction of traditional computational cost. The global significance of alchemical methods lies in their ability to reduce resource consumption, democratise access to high‐level predictions and foster sustainable design of functional materials across diverse sectors.

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Alchemical Approaches in Molecular Design publication trend

The graph below shows the total number of articles in alchemical approaches in molecular design across all publications each year (not limited to Nature Index journals).

Technical terms

Alchemical perturbation theory: A method that treats changes in nuclear charge as a perturbation to compute properties of target molecules from a reference system.

Automatic differentiation: A computational technique for obtaining exact derivatives of complex algorithms with respect to input parameters up to machine precision.

Perturbation density functional theory: An orbital‐free approximation that uses electron density derivatives to estimate energies and properties without self‐consistent field iterations.

Basis set: A set of functions used to represent molecular orbitals in quantum chemical calculations, defined by exponents and contraction coefficients.

Alchemical geometry relaxation: A process that employs mixed alchemical and spatial derivatives to predict relaxed molecular structures efficiently.

References

1. Automatic Differentiation in Quantum Chemistry with Applications to Fully Variational Hartree–Fock. ACS Central Science (2018).
2. Alchemical perturbation density functional theory. Physical Review Research (2020).
3. DQC: A Python program package for differentiable quantum chemistry. The Journal of Chemical Physics (2022).
4. AlxGa1−xAs crystals with direct 2 eV band gaps from computational alchemy. Physical Review Materials (2018).
5. Acceleration of catalyst discovery with easy, fast, and reproducible computational alchemy. International Journal of Quantum Chemistry (2020).
6. Alchemical geometry relaxation. The Journal of Chemical Physics (2022).
7. Extending the definition of atomic basis sets to atoms with fractional nuclear charge. The Journal of Chemical Physics (2024).