Molecular Insights into Phage–Hydrogel Polymer Interactions Through Docking, Molecular Dynamics, and Machine Learning

An efficient bacteriophage delivery system needs to be developed to overcome the challenges associated with phage instability, rapid diffusion, and loss of infectivity at the infection site. Hydrogels have been found to be potential carriers. Hydrogels have emerged as promising carriers due to their biocompatibility, tunable physicochemical properties and capacity for controlled release. However, the molecular factors that regulate phage–hydrogel interactions remain poorly understood. In this study, we employed an in silico framework combining molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding energy calculations, machine learning-based adhesion prediction, and diffusion modeling to explore phage–hydrogel interactions at the molecular level. Surface-exposed bacteriophage proteins, such as capsid and tail proteins, were evaluated against eight different hydrogel polymers. Binding site analysis revealed the presence of multiple solvent-accessible pockets that can interact with the polymer. Docking studies showed favorable and stable interactions, with hyaluronic acid showing strong binding affinity to multiple phage proteins (−5.5 to −5.7 kcal/mol) and GelMA showing high affinity to the capsid gp10 protein (−5.6 kcal/mol). The integrity of the structural complexes was further confirmed by 100 ns MD simulations, stable RMSD and RMSF trajectories, compact structural conformations, and favorable MM/PBSA binding energies. Machine learning classification successfully differentiated high- and low-adhesion systems and identified hydrogen bonding and electrostatic interactions as key determinants of sustained yet reversible phage retention. Collectively, our findings suggest that the hydrogels enriched with charged and polar functional groups can facilitate stable but non-destructive phage binding, enabling controlled and sustained release. This study provides mechanistic insights into rational hydrogel design for phage delivery systems and highlights the potential of high-throughput computational strategies to accelerate the development of optimized phage therapeutics.