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See detailModelling the Extensionally Driven Transitions of DNA
Taghavi, Amirhossein UL

Doctoral thesis (2018)

Empirical measurements on DNA under tension show a jump by a factor of ≈ 1.5 − 1.7 in the relative extension at applied force of ≈ 65 − 70 pN, indi- cating a structural transition. The still ambiguously ... [more ▼]

Empirical measurements on DNA under tension show a jump by a factor of ≈ 1.5 − 1.7 in the relative extension at applied force of ≈ 65 − 70 pN, indi- cating a structural transition. The still ambiguously characterised stretched ‘phase’ is known as S-DNA. Using atomistic and coarse-grained Monte Carlo simulations we study DNA over-stretching in the presence of organic salts Ethidium Bromide (EtBr) and Arginine (an amino acid present in the RecA binding cleft). We present planar-stacked triplet disproportionated DNA as a solution phase of the double helix under tension, and dub it ‘Σ DNA’, with the three right-facing points of the Σ character serving as a mnemonic for the three grouped bases. Like unstretched Watson-Crick base paired DNA structures, the structure of the Σ phase is linked to function: the partitioning of bases into codons of three base-pairs each is the first stage of operation of recombinase enzymes such as RecA, facilitating alignment of homologous or near-homologous sequences for genetic exchange or repair. By showing that this process does not require any very sophisticated manipulation of the DNA, we position it as potentially appearing as an early step in the de- velopment of life, and correlate the postulated sequence of incorporation of amino acids (GADV then GADVESPLIT and then the full 20 residue set of canonical amino acids) into molecular biology with the ease of Σ-formation for sequences including the associated codons. To further investigate the de- pendence of stretching behaviour on the concentration of intercalating salt molecules, we present a physically motivated coarse-grained force-field for DNA under tension and use it to qualitatively reproduce regimes of force- extension behaviour which are not atomistically accessible. [less ▲]

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See detailDNA partitions into triplets under tension in the presence of organic cations, with sequence evolutionary age predicting the stability of the triplet phase
Taghavi, Amirhossein UL; van der Schoot, Paul; Berryman, Josh UL

in Quarterly Reviews of Biophysics (2017), 50

Using atomistic simulations, we show the formation of stable triplet structure when particular GC-rich DNA duplexes are extended in solution over a timescale of hundreds of nanoseconds, in the presence of ... [more ▼]

Using atomistic simulations, we show the formation of stable triplet structure when particular GC-rich DNA duplexes are extended in solution over a timescale of hundreds of nanoseconds, in the presence of organic salt. We present planar-stacked triplet disproportionated DNA (Σ DNA) as a possible solution phase of the double helix under tension, subject to sequence and the presence of stabilising co-factors. Considering the partitioning of the duplexes into triplets of base pairs as the first step of operation of recombinase enzymes like RecA, we emphasise the structure–function relationship in Σ DNA. We supplement atomistic calculations with thermodynamic arguments to show that codons for ‘phase 1’ amino acids (those appearing early in evolution) are more likely than a lower entropy GC-rich sequence to form triplets under tension. We further observe that the four amino acids supposed (in the ‘GADV world’ hypothesis) to constitute the minimal set to produce functional globular proteins have the strongest triplet-forming propensity within the phase 1 set, showing a series of decreasing triplet propensity with evolutionary newness. The weak form of our observation provides a physical mechanism to minimise read frame and recombination alignment errors in the early evolution of the genetic code. [less ▲]

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