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Title: Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms
Abstract Regulatory protein access to the DNA duplex ‘interior’ depends on local DNA ‘breathing’ fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with the experimental spectra. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson–Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.  more » « less
Award ID(s):
1665466
PAR ID:
10262173
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
Nucleic Acids Research
Volume:
49
Issue:
4
ISSN:
0305-1048
Page Range / eLocation ID:
1872 to 1885
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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