Dependence of Ions Transport by DNA Blockage in Alpha-Hemolysin and MspA Toxins Studied by Means of Gran-Canonical Monte-Carlo/Brownian Dynamics with Effective Potentials

Abstract

A recent progress in the development of nanopore technology offers a unique chance for rapid and cost-effective DNA sequencing. Ion-transport dependent on DNA sequence as measured by electrophysiological setup allows relating ion current to a particular nucleotide blocking a narrow nanopore. However, numerous issues make unambiguous sequencing a challenging task. An understanding of molecular underpinning of pore-DNA interactions and relationship between DNA dynamics and resulting ion flow across the pore are among two most important targets for improving already existing nanopores. Several theoretical approaches have been formulated to assist experimental design of the pore ranging from very detailed all-atom MD simulations to models based on a random walk approach. The main challenge for application of all-atom techniques is a limiting time-scale of simulation, while field-based approximations are often lacking atomic-scale resolution. To fill the niche we have developed a novel scheme based on Grand-Canonical Monte-Carlo/Brownian Dynamics simulations and extended it to studies of ion current across two most used in sequencing nanopores, namely alpha-hemolysin and MspA. We also present a protocol for the development of nucleotide-ion effective interacting potentials based on the solution of reverse Monte-Carlo problem as formulated by Lubartzev and colleagues. We show that this inter-mediate resolution method is providing an excellent agreement with experimental results and data from previous studies utilizing computationally expensive Molecular Dynamics simulations.