Protein-Ligand Free Energy Perturbation on Quantum Hardware

Zhen Li; Milana Bazayeva; Thaddeus Pellegrini; Subhamoy Bhowmik; Susanta Das; Danil Kaliakin; Fangchun Liang; Akhil Shajan; Kenneth M. Merz Jr

arXiv · 2604.09857

Protein-Ligand Free Energy Perturbation on Quantum Hardware

Zhen Li·Milana Bazayeva·Thaddeus Pellegrini·Subhamoy Bhowmik·Susanta Das·Danil Kaliakin·Fangchun Liang·Akhil Shajan·Kenneth M. Merz Jr

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Abstract

The use of free energy perturbation (FEP) methods to study protein-ligand complexes is one of the most important tools in structure-based drug design. Because FEP methods typically rely on force fields, they may suffer from force field parameter-related issues. Herein, we present a quantum mechanics/molecular mechanics (QM/MM) hybrid method to overcome deficiencies in force-field models by using QM bookending approaches on both classical and quantum hardware. In the MM part of this QM/MM FEP method, AMBER is used to simulate the protein receptor and the unperturbed moiety of the ligand, with the ff19SB and GAFF2 force fields. In the QM part, QUICK was used to conduct Hartree-Fock (HF) calculations, followed by heat-bath configuration interaction (HCI) as a benchmark on classical devices. To enable the HCI function in QUICK, we developed a Python-based interface to execute HCI from IBM's qiskit-addon-dice-solver. Moreover, the same interface also enabled this work to execute QM/MM FEP calculations on quantum hardware using the Local Unitary Cluster Jastrow (LUCJ) ansatz, followed by sample-based diagonalization (SQD) and extended-SQD (extSQD) post-processing. Using a series of thermolysis inhibitors as an example, we find reasonable agreement with experiment between the classical HCI method and the LUCJ-SQD/extSQD method, with the latter yielding a result closer to the experimental value. The execution time between the HCI-based FEP method and the LUCJ-SQD/extSQD-based FEP method is also comparable, indicating a high potential for utility in the noisy intermediate-scale quantum (NISQ) era.

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Zhen Li, Milana Bazayeva, Thaddeus Pellegrini, Subhamoy Bhowmik, Susanta Das, Danil Kaliakin, Fangchun Liang, Akhil Shajan, Kenneth M. Merz Jr. 2026-04-10. Protein-Ligand Free Energy Perturbation on Quantum Hardware. https://arxiv.org/abs/2604.09857

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