Improving All-Atom Molecular Dynamics Models for Quantitative Prediction of Nanopore Blockade Current

Abstract All-atom molecular dynamics has become an indispensable tool in the development of nanopore sensors of biological information. In a typical nanopore experiment, measurements of ionic current flowing through a nanopore report on the chemical structure of biomolecules that pass through the nanopore. Alone, such experiments are often insufficient to relate the structure of the biomolecules to the ionic current modulations. The molecular dynamics method can establish such a relationship directly through a brute force simulation under an applied electric field. Here, we examine the ability of molecular dynamics force fields to reproduce experimentally measured nanopore blockade currents produced by single-stranded DNA. Our simulations show that none of the “off-the-shelf” force fields (CHARMM36, AMBER Parmbsc1, and DES-AMBER) can reproduce experimental data with the desired level of accuracy. To improve the accuracy, we examined and refined interactions between ions, protein nanopores, and DNA, guided by experiments designed specifically for this purpose. Ultimately, the introduction of surgical corrections to nonbonded interactions within the CHARMM36 force field produced a favorable agreement between simulation and experiment. This refined parameterization, initially developed for nanopore sensing simulations, may have broader applications in computational studies of DNA–protein systems.