Computer Simulations of Biological Change DNA Supercoiling and by murplelake73


     Computer Simulations of Biological Change: DNA Supercoiling and
                          Protein Aggregation
                                          Sarah Anne Harris

                                   School of Physics and Astronomy

                                        University of Leeds, UK

Atomistic molecular dynamics (MD) simulation is an established computational technique that is
widely used to study biomolecular structure, biomolecular dynamics, and molecular recognition.
However, the computational expense of the calculations, which require high performance
supercomputer facilities, place serious limitations on the length and time-scales that can be accessed.
MD simulations of non-equilibrium biological processes are therefore particularly challenging at the
atomistic level. Using parallel MD codes and supercomputing facilities, we are investigating
biological change in a variety of systems; in particular DNA supercoiling, and amyloid fibril

Although the discovery of the structure of duplex DNA revealed how cells store genetic information,
we are still far from understanding the more complex biological question of how this information is
regulated and processed by the cell. DNA topology and supercoiling is known to affect DNA
transcription and other DNA-associated processes. Small DNA circles offer a controllable model
system for the systematic exploration of the dependence of DNA structure on supercoiling, both
experimentally and theoretically. We use atomistic MD to explore the supercoiling-dependent
conformation of small DNA circles, and how this is affected by supercoiling, salt concentration, DNA
sequence, the size of the circles and their interactions with other biomolecules1.

As well as undergoing large conformational changes, such as changes in DNA topology, biomolecules
are also capable of self-assembling into highly organised structures. Many peptides and proteins
aggregate into long filamentous structures know as amyloid fibrils under the appropriate experimental
conditions. The formation of these fibres is implicated in a number of human diseases, including
Alzheimer’s disease and Creutzfeldt-Jakob disease. We use atomistic MD to construct and test in
silico models of amyloid-like peptide aggregates to investigate amyloid polymorphism; namely how
the same peptide sequence can aggregate into fibrils with differing morphologies2.

As computer hardware and software continues to improve, and longer time-scales become accessible
to atomistic simulation, MD calculations will increasingly be used to study biological change.
1.   Harris S. A., Laughton C. A. & Liverpool T. B. “Mapping the phase diagram of the writhe of DNA
     nanocircles using atomistic molecular dynamics simulations” (2008) Nucleic. Acids. Res. 36, 21-29.
2.   Berryman J. T., Radford S. E & Harris S. A. “Thermodynamic description of polymorphism in Q- and N-
     rich peptide aggregates revealed by atomistic simulation” (2009) Biophys. J. 97, 1-11.

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