Force Field and Membrane Patch Size Effects on Atomistic Models of Aquaporin-7

Molecular dynamics (MD) simulations are a powerful tool for characterizing membrane-protein dynamics, yet their predictive accuracy critically depends on the choice of force field and membrane representation. Here, we present a systematic benchmark of the AMBER 14SB and CHARMM 36 m force fields across multiple bilayer sizes, using human aquaporin-7 (aquaglyceroporin-7; hAQP7) as a representative membrane protein system. Both force fields maintained global structural integrity, but differed markedly in their dynamic profiles: CHARMM 36 m sampled a broader conformational space and produced more hydrated pore profiles, whereas AMBER 14SB favored conformations closer to the crystallographic structure. Lipid organization and packing also diverged, with CHARMM generating more compact bilayers and AMBER yielding larger areas per lipid. The membrane size exerted minimal influence on the structural or functional descriptors, supporting the use of smaller, computationally efficient membrane patches for equilibrium simulations. The hAQP7 monomers functioned independently, without detectable cooperativity under the simulated conditions. Collectively, these results highlight the substantial impact of force-field selection on aquaporin dynamics and provide practical guidance for designing accurate MD simulations of transmembrane protein channels.