Biomedical Engineering Reference
In-Depth Information
complex cannot be simulated by the MD method if the mean rupture time approaches
the timescale of experiment. Among other processes difficult to model are the capture
of analytes from solution by the nanopore and spontaneous dissociation of biomolec-
ular assemblies, for example spontaneous unzipping of hairpin DNA, which could be
relevant for nanopore translocation under some experimental conditions. Further-
more, the computational expense of large-scale MD runs can sometimes preclude
the gathering of statistical data. We are sometimes left with making qualitative
conclusions from a handful of trajectories, rather than quantitative results that
could be obtainable by analyzing hundreds of trajectories.
Another factor that limits the predictive power of MD simulations is the accu-
racy of the molecular force field that describes the interactions between atoms in the
simulation. One notable example of erroneous results due to force fields concerns
the popular AMBER parm99 force field, with which DNA structures known to be
stable in experiment made irreversible transitions to implausible structures in
sufficiently long MD simulations [
34
]. Simulations of NSF experiments performed
using this force field and its modified version [
34
] (that did not exhibit the spurious
transitions) have shown some quantitative differences, while the qualitative behav-
ior was preserved [
20
]. The force fields used to describe the surfaces of synthetic
nanopores are particularly suspect as their interaction with DNA has not been
calibrated. Furthermore, the composition and the structure of the synthetic
nanopore surfaces themselves are not well known and depend on the fabrication
methods [
66
].
Future advances in computer technology, simulation methods, and force fields
will likely erase some problems that limit the application of the MD method to NFS
today. As simulations in the microsecond range become routine, it will become
possible to study NFS for processes in which phenomena such as spontaneous
partial unfolding of proteins and nucleic acids are important. However, we strongly
believe that MD simulation coupled with NFS experiments can even today form a
single tool for the elucidation of biological phenomena and development of bio-
technology that is more than a sum of its parts.
Acknowledgements We gratefully acknowledge contributions from Gregory Sigalov, Binquan
Luan, and the group of Gregory Timp. This work is supported by grants from the National Institutes
of Health (R01-HG003713 and PHS 5 P41-RR05969) and the National Science Foundation
(PHY0822613). The authors gladly acknowledge supercomputer time provided through TeraGrid
resources by a Large Resources Allocation grant (MCA05S028).
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