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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.

SUBMITTER: Beyerle ER

PROVIDER: S-EPMC7913701 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms.

Beyerle Eric R ER Dinpajooh Mohammadhasan M Ji Huiying H von Hippel Peter H PH Marcus Andrew H AH Guenza Marina G MG

Nucleic acids research 20210201 4

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-unstacki ...[more]

PMID: 33503257

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Project description:Base stacking is known to make an important contribution to the stability of DNA and RNA, and accordingly, significant efforts are ongoing to calculate stacking energies using ab initio quantum mechanical methods. To date, impressive improvements have been made in the model chemistries used to perform stacking energy calculations, including extensions that include robust treatments of electron correlation with extended basis sets, as required to treat interactions where dispersion makes a significant contribution. However, those efforts typically use rigid monomer geometries when calculating the interaction energies. To overcome this, in the present work, we describe a novel internal coordinate definition that allows the relative, intermolecular orientation of stacked base monomers to be constrained during geometry optimizations while allowing full optimization of the intramolecular degrees of freedom. Use of the novel reference frame to calculate the impact of full geometry optimization versus constraining the bases to be planar on base monomer stacking energies, combined with density-fitted, spin-component scaling MP2 treatment of electron correlation, shows that full optimization makes the average stacking energy more favorable by -3.4 and -1.5 kcal/mol for the canonical A and B conformations of the 16 5' to 3' base stacked monomers. Thus, treatment of geometry optimization impacts the stacking energies to an extent similar to or greater than the impact of current state of the art increases in the rigor of the model chemistry itself used to treat base stacking. Results also indicate that stacking favors the B-form of DNA, though the average difference versus the A-form decreases from -2.6 to -0.6 kcal/mol when the intramolecular geometry is allowed to fully relax. However, stacking involving cytosine is shown to favor the A-form of DNA, with that contribution generally larger in the fully optimized bases. The present results show the importance of allowing geometry optimization, as well as properly treating the appropriate model chemistry, in studies of nucleic acid base stacking.

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Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms.

Publications

Dinucleotides as simple models of the base stacking-unstacking component of DNA 'breathing' mechanisms.

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