QFoldAgent: An Autonomous Quantum Optimization Multi-Agent System for Protein Structure Prediction

Hybrid quantum-classical protein structure prediction depends strongly on Hamiltonian penalty weights, yet existing lattice-based workflows typically fix these coefficients by hand and evaluate only very short fragments in simulation.

We present QFoldAgent, a closed-loop multi-agent framework for 5-residue tetrahedral-lattice folding in which a design agent proposes sequence-conditioned penalties, a VQE-based quantum-classical pipeline optimizes the resulting Hamiltonian under Qiskit Aer noise, and a feedback agent uses energy-landscape diagnostics and MolProbity validation signals to refine penalties across cycles.

Ground-truth metrics such as RMSD are never exposed to the agents and are used only for evaluation.

We study the framework on two complementary datasets: 55 QDockBank-derived fragments with known structures and 100 coverage-optimized unseen sequences.

On the QDockBank benchmark, QFoldAgent reduces median RMSD from 3.64 Å to 3.20 Å, with the largest gains on the hardest targets.

On unseen sequences, the closed loop raises structural validity from 87.5% to 98.7%, recovers 87% of initially invalid cases, and the strongest controller improves cycle-3 energy on 87% of sequences while maintaining 96% Ramachandran-favored geometry.

These results show that iterative agent control can systematically improve optimization behavior and reduce failure cases in a 5-residue quantum setting.