A ligand can adopt multiple conformations within the same binding site, and these conformations can interact differently with the surrounding protein. Multiconformer modeling must therefore determine which candidate conformations to retain and what occupancies to assign to them. An established automated approach uses mixed-integer quadratic programming (MIQP) with hard occupancy and conformer-count limits for this selection. Here, we reformulated conformer selection as a quadratic unconstrained binary optimization (QUBO) problem with finite penalties and discrete occupancies. We solved the QUBO using a quantum-classical hybrid solver. We compared this workflow with the MIQP-based qFit-ligand workflow across 83 paired X-ray ligand entries using the same experimental inputs and the same qFit-ligand processing protocol. For each entry, both final models were evaluated against the same composite-omit map generated from the common input structure before the two workflows diverged. Quantum-qFit produced higher ligand-region real-space correlation coefficients (RSCC) in 62 entries 74.7% and lower occupancy-weighted torsional strain in 66 entries 79.5%. Similar directional trends remained in the 28 entries with matched final conformer counts. The molecular Electron Density for Individual Atoms score (EDIAm) decreased in most entries. This result shows that higher regional map agreement did not necessarily correspond to stronger atom-level density support. Overall, the results show that the conformer-selection formulation can change which ligand states are represented from the same experimental data and provide a QUBO framework for studying multiconformer ligand selection.
A ligand can adopt multiple conformations within the same binding site, and these conformations can interact differently with the surrounding protein. Multiconformer modeling must therefore determine which candidate conformations to retain and what occupancies to assign to them. An established automated approach uses mixed-integer quadratic programming (MIQP) with hard occupancy and conformer-count limits for this selection. Here, we reformulated conformer selection as a quadratic unconstrained binary optimization (QUBO) problem with finite penalties and discrete occupancies. We solved the QUBO using a quantum-classical hybrid solver. We compared this workflow with the MIQP-based qFit-ligand workflow across 83 paired X-ray ligand entries using the same experimental inputs and the same qFit-ligand processing protocol. For each entry, both final models were evaluated against the same composite-omit map generated from the common input structure before the two workflows diverged. Quantum-qFit produced higher ligand-region real-space correlation coefficients (RSCC) in 62 entries 74.7% and lower occupancy-weighted torsional strain in 66 entries 79.5%. Similar directional trends remained in the 28 entries with matched final conformer counts. The molecular Electron Density for Individual Atoms score (EDIAm) decreased in most entries. This result shows that higher regional map agreement did not necessarily correspond to stronger atom-level density support. Overall, the results show that the conformer-selection formulation can change which ligand states are represented from the same experimental data and provide a QUBO framework for studying multiconformer ligand selection.
Abstract As interest in quantum and related optimization paradigms continues to grow, fairly and systematically comparing their performance across practical problem settings remains challenging. This challenge arises because these approaches often target different problem classes, use different mathematical representations, and are affected differently by modeling choices. As a result, observed performance depends not only on the solver itself, but also on how a problem is formulated, reformulated, and translated into a solver-specific input language. This work presents a publicly available and extensible benchmarking framework that unifies advances in quantum, quantum-hybrid, quantum-inspired, and classical optimization by enabling consistent comparison across use cases, solvers, and models. We address the diversity of solver “languages”—from mixed-integer programming (MIP) formulations for branch-and-bound methods over quadratic unconstrained binary optimization (QUBO) models for quantum annealers to constrained quadratic models (CQM) for hybrid approaches — as well as the influence of modeling choices, such as binary encodings and penalty formulations, on both performance and solution fidelity. By supporting systematic variation across the three dimensions of use case, solver, and model, the framework reveals trade-offs that single-dimension benchmarks overlook, clarifies when native formulations are preferable, and enables rigorous evaluation of practical combinatorial optimization problems. The two case studies, vehicle routing and maximum cut, illustrate this principle: their contrasting outcomes show that the effectiveness of a solver depends strongly on how well the chosen model representation matches the solver backend and the use case.
Quadratic Unconstrained Binary Optimization (QUBO) is a central formulation for combinatorial optimization and has gained increasing attention due to its compatibility with quantum, hybrid quantum-classical, and quantum-inspired solvers. However, translating natural-language problem descriptions into correct QUBO formulations remains difficult, requiring the identification of binary variables, constraints, objective functions, penalty terms, and suitable penalty weights. This process is time-consuming and often demands substantial domain expertise. To address this challenge, we propose an end-to-end multi-agent framework that automatically generates QUBO formulations from natural-language problem descriptions, supported by structured or unstructured test cases. To evaluate its performance, We also introduce QUBOBench, a benchmark containing 100 combinatorial optimization problems across 12 application domains, curated from peer-reviewed literature, competitions, and canonical NP-hard problems. Experimental results show that our framework achieves 68% accuracy on QUBOBench, outperforming a direct single-call baseline by 22%. Further analysis identifies iterative self-repair as the most important component contributing to improved performance. The data and code are open-sourced at https://quitttcat.github.io/QuantumQUBOAgent.
Demonstrating the practical utility of Noisy Intermediate-Scale Quantum (NISQ) hardware for recurrent tasks in Computer-Aided Drug Discovery is of paramount importance. We tackle this challenge by performing three-dimensional protein pockets hydration-site prediction on a quantum computer. Formulating the water placement problem as a Quadratic Unconstrained Binary Optimization (QUBO), we use a hybrid approach coupling a classical three-dimensional reference-interaction site model (3D-RISM) to an efficient quantum optimization solver, to run various hardware experiments up to 123 qubits. Matching the precision of classical approaches, our results reproduced experimental predictions on real-life protein-ligand complexes. Furthermore, through a detailed resource estimation analysis, we show that accuracy can be systematically improved with increasing number of qubits, indicating that full quantum utility is in reach. Finally, we provide evidence that advantageous situations could be found for systems where classical optimization struggles to provide optimal solutions. The method has potential for assisting simulations of protein-ligand complexes for drug lead optimization and setup of docking calculations.
Sidechain packing is a critical stage in protein folding, with direct implications for structure-based drug discovery. Google DeepMind's tool, AlphaFold2, predicts protein backbone reliably but sidechain positioning less accurately. Recovering the lowest-energy rotamer assignment over a fixed backbone is NP-hard. We present a hybrid quantum-classical pipeline that repacks sidechains on the AlphaFold backbone using the Quantum Approximate Optimisation Algorithm (QAOA), encoding the one- and two-body energies as a quadratic unconstrained binary optimisation (QUBO) problem. We introduce a constraint-preserving ansatz, pairing a W-state initialisation with a cyclic XY ring mixer, that enforces one-hot rotamer validity without penalty terms while keeping two-qubit gate scaling linear in the rotamer count. We also define an asymptotic shot-scaling metric, measured against the experimentally resolved conformation, that fixes optimiser quality independently of the baseline; its fitted growth stays below the classical exhaustive-search rate at moderate rotamer flexibility. Evaluated on bovine pancreatic trypsin inhibitor (5PTI) across high- and moderate AlphaFold-confidence regions, the pipeline lowers conformational energy against the AlphaFold baseline.
Quantum optimization provides a promising approach for solving large-scale combinatorial problems through quadratic unconstrained binary optimization (QUBO) formulations. However, integrating QUBO-based solvers into structured optimization frameworks while preserving solution guarantees remains a fundamental challenge. This paper develops a hybrid quantum-classical column-and-constraint generation (QCCG) framework for solving two-stage adaptive robust optimization problems with binary first-stage decisions and linear recourse under polyhedral uncertainty. The proposed approach reformulates the restricted master problem as a QUBO and solves it approximately using a quantum optimizer, while retaining a classical adversarial subproblem to compute worst-case recourse and certify solution quality. We construct a constraint-preserving QUBO encoding for inequality-constrained master problems using slack variables and penalty terms, enabling general mixed-integer structures to be mapped to quantum-compatible representations. To address inexactness arising from discretization, penalty modeling, and quantum optimization, we introduce a bound-adjustment mechanism that yields valid lower and upper bounds and provides a certified stopping criterion. We show that the proposed framework generalizes classical column-and-constraint generation and retains its convergence properties when the master problem is solved exactly. Numerical experiments on two-stage robust location-transportation problems demonstrate that the proposed hybrid approach achieves solution quality comparable to classical methods while reducing the computational burden associated with solving mixed-integer master problems, highlighting the potential of hybrid quantum-classical optimization for scalable decision-making under uncertainty.
Quantum annealing and related combinatorial optimization methods typically accept quadratic unconstrained binary optimization (QUBO) problems as input, whereas many practical models include constraints and continuous variables. Standard QUBO conversions discretize continuous variables, increasing the binary dimension and often making feasible low-energy states harder to sample. We develop a Lagrange-multiplier method for a separable class of mixed-binary quadratic programs (MBQPs) without discretizing continuous variables. The method is based on a finite-temperature free-energy formulation and uses QUBO sampling for the binary sector. At fixed Lagrange multipliers, the continuous sector is integrated out analytically and enters only the multiplier update, leaving a QUBO over the original binary variables. We evaluate the method on the continuous relaxation of the quadratic p-median problem. Compared with a penalty-based QUBO formulation, it generates feasible solutions more reliably. At an appropriate inverse temperature, its conditional relative error is comparable to that of local search for small instances and often lower for the larger tested instances. In the time-to-target comparisons, the proposed method maintains high target-reached rates for stringent fixed-accuracy targets. For the larger instances within the tested range, it also reaches the prescribed targets faster than a commercial mixed-integer optimization solver.