Biomolecular transport through nanopores is central to biological processes and emerging biotechnologies. While biological nanopores (1–2 nm) have advanced peptide sequencing, their limited operational stability (tens of minutes) constrains practical applications. Solid-state nanopores fabricated from silicon nitride (Si 3 N 4 ) offer superior mechanical robustness and reproducibility, yet folded protein translocation through wider apertures (>10 nm) remains poorly characterized. We employ a multiscale framework integrating Brownian dynamics (BD) and all-atom molecular dynamics (AA-MD) to investigate protein transport through a 20-nm Si 3 N 4 nanopore under applied electric fields, using human ferritin and ribonuclease as model systems. BD simulations characterize the long-range capture process, quantifying how capture radius, capture time, and capture efficiency vary with pH, voltage, ionic strength, and protein identity. By sampling this capture phase, BD generates statistical distributions of protein conformations and orientations at the pore entrance, thereby providing initial conditions for subsequent AA-MD simulations. At atomic resolution, AA-MD then elucidates protein-pore interactions, conformational dynamics, and potential trapping mechanisms governed by charge distribution, molecular weight, and surface chemistry. These atomistic insights inform subsequent BD simulations, extending sampling to millisecond timescales and generating statistically robust ensembles of translocation trajectories and ionic current signatures. This integrated approach highlights the complementary strengths of BD and AA-MD, yielding a unified picture of folded protein transport through wide solid-state nanopores and establishing a versatile platform for nanopore-based protein detection and characterization.
Yang et al. (Sun,) studied this question.
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