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Title: Intrinsic curvature of DNA : a molecular dynamics study.
Author: Norberto de Souza, Osmar
ISNI:       0000 0001 3473 3948
Awarding Body: Birkbeck (University of London)
Current Institution: Birkbeck (University of London)
Date of Award: 1994
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DNA intrinsic curvature is, at present, one of the major topics of research concerning DNA conformation and dynamics because of its implications in phenomena of great biological relevance including transcription activation and chromatin packaging. DNA sequences containing runs of adenines residues (A-tracts) are of central importance to this phenomenon since the length of the A-tracts and their phasing with the helix screw significantly alter the curvature profile of DNA. X-ray crystallography of DNA single crystals has provided a wealth of information about the local, short range conformational features of general-sequence and also A-tractcontaining DNA oligomers but it lacks the same strength in the analysis of long range conformational features of DNA. On the other hand, gel-electrophoresis analysis of DNA has not only uncovered the macroscopic curvature of DNA but it also provides most of the available data on DNA intrinsic curvature. However, gel electrophoresis can not identify features of DNA structure at the nucleotide or atomic level. This work is an attempt of bridging the gap between such techniques by using the method of molecular dynamics (MD) simulations. MD simulations were performed on 5 A-tract-containing dodecamers, 3 of which have available crystal structures, and on a 51 base-pair DNA fragment from the kinetoplast DNA of Leishmania tarentolae. The results shows that A-tracts can be strongly curved, contrary to what is expected from X-ray analysis of DNA single crystals. The detailed analysis of the MD trajectories also shows that DNA curves towards the major groove. An explanation which demonstrate the consistence between major groove curvature and uncurving of DNA upon binding of the antibiotic distamycin is provided. Furthermore, regions of hyperflexibility or junctions between A-tracts and general-sequence DNA are identified and shown to modulate DNA intrinsic curvature. The flexibility pattern of the sugar rings can provide an alternative explanation for the cleavage pattern of A-tract-containing DNA by the hydroxyl radical. An attempt to predict the curvature of other A-tract-containing DNA sequences is also presented. It is shown that, in order to realistically represent the curvature of A-tract-containing DNA, the intrinsic structure of individual A-tracts must be preserved and not averaged as in the Wedge model. Finally, some computer experiments are suggested in order to refine our knowledge of DNA conformation and dynamics using MD simulations before such technique can be routinely used in the investigation of phenomena of biological and medicinal relevance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics