Nanopore Force Spectroscopy: Insights from Molecular Dynamics Simulations - Nanopores: Sensing and Fundamental Biological Interactions - page 339

Another difficulty of NFS is interpretation of the measured ion current signatures
in terms of microscopic events in the pore. While some ion current signatures may
be easy to interpret, such as a reduction in the current caused by the presence of
DNA threading through the pore, a rich variety of current signatures have been
observed in nanopore experiments. The ion current through nanopores containing
DNA has been heavily studied [ 29 ]. It is understood that the effect of the DNA on
the current is a competition between two effects: steric blockage of the pore by
DNA, which decreases the current, and enhancement of the density of charge
carriers due to the DNA's counterions, which increases the current [ 30 , 31 ]. At
high bulk ion concentrations, the first effect dominates and the current is reduced by
the DNA. At low bulk ion concentrations, the second effect dominates and the
current is enhanced. However, in some cases, both enhancements and reductions
are seen under the same macroscopic conditions [ 18 , 20 , 31 ]. This suggests that the
ion current depends on microscopic details of the DNA conformation in the pore.
14.1.2 Molecular Dynamics Simulation
Molecular Dynamics (MD) simulation, by providing an atomic resolution view of
the processes occurring in the pore, has the ability to fill some of the gaps in the
information furnished by NFS experiments. MD simulations can yield predictions of
how the analyte interacts with the pore, what conformation the analyte is likely to
have during different stages of the experiment, and sequences in which events such
as dissociation are likely to occur. For example, if one were studying unzipping of
DNA duplexes, one could estimate how deeply the duplex penetrates into the pore
during the experiment, how much the duplex stretches at various transmembrane
voltages, and which basepairs of the duplex are likely to break first under the applied
force. Although NFS experiments rarely allow direct measurement of the forces
applied to analyte, these forces can be calculated in MD simulations. Furthermore,
MD allows us to observe the microscopic details of processes occurring in the
nanopore, while simultaneously obtaining estimates of the ion current through
the nanopore. We can therefore associate ranges of current values with specific
molecular configurations of the analyte in the pore. The topic of interpretation of ion
current signatures has been reviewed elsewhere [ 29 ]; however, considering its
importance to NFS experiments, we describe some of the pertinent aspects here.
This chapter focuses on classical all-atom MD, which we will refer to simply as
MD, although ab initio MD, which employs approximations to quantum mechani-
cal laws, and coarse-grain MD, in which groups of atoms are represented by single
simulated particles, could also be useful. MD simulations typically begin with
the creation of a computational model of a small key portion of the experiment.
For simulations of NFS in synthetic nanopores, we begin with a three-dimensional
simulation cell having linear dimensions of a few tens of nanometers to comfortably
accommodate the structures of interest. Atomic-resolution models of biomolecules,
often constructed using data from X-ray crystallography or nuclear magnetic