Quantum Computing for Electronic Circular Dichroism Spectrum Prediction of Chiral Molecules

TL;DR

This work tackles the challenge of predicting electronic circular dichroism (ECD) spectra for chiral molecules from first principles with scalable, physics-based methods. It introduces a hybrid quantum–classical workflow that combines a variational quantum eigensolver (VQE) for ground states with a quantum equation-of-motion (qEOM) treatment for excited states within an active-space framework, mapped to approximately $20$–$24$ qubits and accelerated by multi-GPU hardware. The methodology is benchmarked against classical CASCI references (and CCSD for ground states) across 12 pharmaceutically relevant chiral drugs, achieving near-quantitative agreement in spectral shapes, Cotton-effect signs, and relative peak intensities for both single- and multi-chiral-center systems, with minor deviations arising in densely packed spectra. This approach demonstrates a scalable, first-principles route to ECD prediction that can extend to larger, more complex molecules, supporting reliable chiral assignment and drug-design workflows as quantum hardware advances.

Abstract

Electronic circular dichroism (ECD) spectroscopy captures the chiroptical response of molecules, enabling absolute configuration assignment that is vital for enantioselective synthesis and drug design. The practical use of ECD spectra in predictive modeling remains restricted, as existing approaches offer limited confidence for chiral discrimination. By contrast, theoretical ECD calculations demand substantial computational effort rooted in electronic structure theory, which constrains their scalability to larger chemically diverse molecules. These limitations underscore the need for computational approaches that retain first principles physical rigor while enabling efficient and scalable prediction. Motivated by recent advances in quantum algorithms for chemistry, we introduce a variational quantum framework combined with the quantum equation of motion formalism to compute molecular properties and predict ECD spectra, implemented within a multi GPU or QPU accelerated hybrid quantum/classical workflow. We demonstrate its efficient applicability on 12 clinically relevant chiral drug molecules accessing expanded active spaces. The proposed framework is assessed by comparison with established classical wavefunction based methods, employing Coupled Cluster Singles and Doubles (CCSD) for ground-state energy benchmarks and Complete Active Space Configuration Interaction (CASCI) as the reference method for excited state energies and chiroptical properties within the same active orbital space. Notably, the quantum computed ECD spectra, obtained from chemically relevant active spaces mapped onto quantum circuits of approximately 20 to 24 qubits, exhibit near quantitative agreement with classical reference calculations, accurately reproducing spectral line shapes, Cotton effect signs, and relative peak intensities.

Figures (10)

• Figure 1: Enantioselectivity determines drug efficacy and safety. Ibuprofen is a commonly prescribed nonsteroidal anti-inflammatory drug used to treat pain, inflammation, and fever in both adults and pediatric patients, with therapeutic activity arising from the (S)-enantiomer. Thalidomide displays opposite enantioselective effects, as its (R)-enantiomer exhibits sedative effects in patients, whereas exposure to the (S)-enantiomer during pregnancy results in teratogenic effects affecting fetal development.
• Figure 2: The Schematic representation of the ECD prediction and chiral assignment. Electronic Circular Dichroism (ECD) comparison is widely used for absolute configuration assignment, but theoretical ECD simulations are computationally demanding due to conformational screening, geometry optimization, excited-state calculations, and Boltzmann-weighted averaging. Deep-learning–based approaches enable accelerated ECD prediction but often lack quantitative accuracy and transferability; this motivates the variational quantum algorithm presented here, which computes ECD spectra using multi-GPU- and QPU-accelerated quantum–classical workflows within an active-space framework and is validated against CASCI.
• Figure 3: Quantum-classical workflow for computing electronic circular dichroism (ECD) spectra of chiral drug molecules. (a) Molecular structure of a representative chiral pharmaceutical compound. (b) Selection of the active orbital subspace based on natural occupation numbers, retaining orbitals with occupations in the range $0.02 \le n_i \le 1.98$ to capture essential static and dynamic correlation effects. (c) Construction of the active-space electronic Hamiltonian and its mapping to a qubit representation using fermionic second-quantized operators followed by the Jordan--Wigner transformation. (d) Ground-state energy optimization using the VQE, where a parametrized quantum circuit is iteratively optimized by a classical optimizer until convergence. (e-f) Evaluation of excited-state energies via the qEOM formalism built upon the converged VQE reference state. (g) Computation of electric and magnetic transition dipole moments and rotatory strengths from qEOM excited states, (h) leading to the final ECD spectrum.
• Figure 4: Convergence of the variational quantum eigensolver (VQE) ground-state energy relative to the exact reference solution for representative chiral molecules. The top row shows the ground-state energy (in Hartree) as a function of the number of optimization iterations for the (a) R-omeprazole, (b) R-ketoprofen, and (c) R-D-ribose enantiomers. The bottom row presents the corresponding convergence behavior for the S-enantiomers of each molecule. In all panels, the VQE energies are compared against exact solver results, illustrating the convergence characteristics and accuracy of the VQE approach across different chiral systems.
• Figure 5: Quantum prediction of electronic circular dichroism in chiral molecules. Top: R- and S-enantiomers of D-ribose with ECD spectra computed using the VQE–qEOM framework, showing mirror-image responses and quantitative agreement with classical CASCI results in the CAS(12,12) active space mapped to 24 qubits. Bottom: ECD spectra of chiral omeprazole obtained with VQE–qEOM, exhibiting close agreement with CASCI reference calculations. The quantum results show very close agreement with classical CASCI reference calculations, accurately reproducing the sign, relative intensity, and spectral features of the ECD response.