Scalable Decoupling Contact and Configuration Spaces in a Quantum-Enabled Protein Folding Workflow

Abstract

Near-term quantum devices remain constrained by limited qubit counts, noise, and shallow circuit depth, restricting their direct application to peptide folding. This work addresses this limitation through a hybrid quantum–classical framework that separates global contact-space exploration from local configuration-space refinement. The pipeline was evaluated on the p53 transactivation peptide. The peptide was encoded using discrete torsional states and Miyazawa–Jernigan contact potentials. Global conformational search was performed using simulated annealing, followed by fragment-level CVaR-based variational quantum eigensolver refinement. Overlapping fragments were stitched and reconstructed into three-dimensional backbone coordinates for structural comparison. Three independent simulated annealing restarts produced negative-energy conformers. The workflow identified a best global conformer at E = −3.70 MJ using simulated annealing. Fragment-level CVaR-VQE refinement generated 30 candidate conformers across three overlapping fragments, the best assembled conformer reaching E = −2.58 MJ after DP stitching and post-stitch refinement. In this trial, the classical SA solution outperformed the VQE-assembled structure and was selected as the final output. The final 65-atom model was successfully reconstructed, but full-backbone alignment against 1YCR yielded an RMSD of 4.65 Å, improving to 2.90 Å after trimmed alignment. Our work demonstrates a practical quantum-enabled peptide folding workflow for short, flexible peptides, but the present structural accuracy is insufficient for claims of native fold recovery. Its main value is as an auditable framework for testing NISQ-compatible folding strategies.