Modeling Polymer Interactions with Nanopores for DNA Sequencing and Proteomics Applications

Abstract

Protein beta-barrel nanopores have been used to characterize a wide variety of molecules including polyethylene glycol (PEG), deoxyribonucleic acid (DNA) and polypeptides - a potentially significant step in realizing low cost sequencing of DNA, as well as in proteomics. Simulations can improve our understanding of the conformation and dynamics of polymers inside a nanopore, which we believe are significant to properly interpret experimental data. However, in an effort to overcome the limitations of time scales associated with all-atom molecular dynamics simulations we introduce two simplified models for PEG in α-hemolysin. Both represent the nanopore by a grid potential calculated from the Poisson-Boltzmann equation, and contain explicit ions and flexible PEG. One model includes water implicitly with a short-range water mediated potential of mean force to correctly account for ion-ion interactions; the other contains explicit TIP3 water. We also present a third, even simpler model with rigid PEG in the pore, where the ionic current blockade differs from experiment significantly highlighting the importance of the dynamics of PEG inside the pore. We then compare results from the first two simulation models with those from an all-atom simulation. Finally, we compare the depth of the ionic current blockade associated with PEG binding from each model with experimental results.