Christophe Oguey

Understanding the sequence-dependence of DNA groove dimensions: implications for DNA interactions.

Background The B-DNA major and minor groove dimensions are crucial for DNA-protein interactions. It has long been thought that the groove dimensions depend on the DNA sequence, however this relationship has remained elusive. Here, our aim is to elucidate how the DNA sequence intrinsically shapes the grooves. Methodology/Principal Findings The present study is based on the analysis of datasets of free and protein-bound DNA crystal structures, and from a compilation of NMR 31P chemical shifts measured on free DNA in solution on a broad range of representative sequences. The 31P chemical shifts can be interpreted in terms of the BI↔BII backbone conformations and dynamics. The grooves width and depth of free and protein-bound DNA are found to be clearly related to the BI/BII backbone conformational states. The DNA propensity to undergo BI↔BII backbone transitions is highly sequence-dependent and can be quantified at the dinucleotide level. This dual relationship, between DNA sequence and backbone behavior on one hand, and backbone behavior and groove dimensions on the other hand, allows to decipher the link between DNA sequence and groove dimensions. It also firmly establishes that proteins take advantage of the intrinsic DNA groove properties. Conclusions/Significance The study provides a general framework explaining how the DNA sequence shapes the groove dimensions in free and protein-bound DNA, with far-reaching implications for DNA-protein indirect readout in both specific and non specific interactions.

Intrinsic flexibility of B-DNA: the experimental TRX scale

B-DNA flexibility, crucial for DNA–protein recognition, is sequence dependent. Free DNA in solution would in principle be the best reference state to uncover the relation between base sequences and their intrinsic flexibility; however, this has long been hampered by a lack of suitable experimental data. We investigated this relationship by compiling and analyzing a large dataset of NMR 31P chemical shifts in solution. These measurements reflect the BI ↔ BII equilibrium in DNA, intimately correlated to helicoidal descriptors of the curvature, winding and groove dimensions. Comparing the ten complementary DNA dinucleotide steps indicates that some steps are much more flexible than others. This malleability is primarily controlled at the dinucleotide level, modulated by the tetranucleotide environment. Our analyses provide an experimental scale called TRX that quantifies the intrinsic flexibility of the ten dinucleotide steps in terms of Twist, Roll, and X-disp (base pair displacement). Applying the TRX scale to DNA sequences optimized for nucleosome formation reveals a 10 base-pair periodic alternation of stiff and flexible regions. Thus, DNA flexibility captured by the TRX scale is relevant to nucleosome formation, suggesting that this scale may be of general interest to better understand protein-DNA recognition.

Importance of accurate DNA structures in solution: the Jun-Fos model.

Understanding the recognition of DNA sequences by proteins requires an accurate description of the structural dynamics of free DNA, especially regarding indirect readout. This involves subtle sequence-dependent effects that are difficult to characterize in solution. To progress in this area, we applied NMR and extensive simulations to a DNA sequence relevant to the Jun-Fos system. The backbone and base behaviors demonstrate that unrestrained simulations with major force fields (Parm98, Parmbsc0, and CHARMM27) are not reliable enough for in silico predictions of detailed DNA structures. More realistic structures required molecular dynamics simulations supplemented by NMR restraints. A new methodological element involved restraints inferred from the phosphate chemical shifts and from the phosphate dynamics. This provided a detailed and dynamic view of the intrinsic properties of the free DNA sequence that can be related to its recognition, by comparison with a relevant DNA-protein complex. We show how to exploit the relationship between phosphate motions and helicoidal descriptors for structure determination toward an accurate description of DNA structures and dynamics in solution.

From 2D hyperbolic forests to 3D Euclidean entangled thickets

Abstract:A method is developed to construct and analyse a wide class of graphs embedded in Euclidean 3D space, including multiply-connected and entangled examples. The graphs are derived via embeddings of infinite families of trees (forests) in the hyperbolic plane, and subsequent folding into triply periodic minimal surfaces, including the P, D, gyroid and H surfaces. Some of these graphs are natural generalisations of bicontinuous topologies to bi-, tri-, quadra- and octa-continuous forms. Interwoven layer graphs and periodic sets of finite clusters also emerge from the algorithm. Many of the graphs are chiral. The generated graphs are compared with some organo-metallic molecular crystals with multiple frameworks and molecular mesophases found in copolymer melts.

Simulations Meet Experiment to Reveal New Insights into DNA Intrinsic Mechanics

The accurate prediction of the structure and dynamics of DNA remains a major challenge in computational biology due to the dearth of precise experimental information on DNA free in solution and limitations in the DNA force-fields underpinning the simulations. A new generation of force-fields has been developed to better represent the sequence-dependent B-DNA intrinsic mechanics, in particular with respect to the BI ↔ BII backbone equilibrium, which is essential to understand the B-DNA properties. Here, the performance of MD simulations with the newly updated force-fields Parmbsc0εζOLI and CHARMM36 was tested against a large ensemble of recent NMR data collected on four DNA dodecamers involved in nucleosome positioning. We find impressive progress towards a coherent, realistic representation of B-DNA in solution, despite residual shortcomings. This improved representation allows new and deeper interpretation of the experimental observables, including regarding the behavior of facing phosphate groups in complementary dinucleotides, and their modulation by the sequence. It also provides the opportunity to extensively revisit and refine the coupling between backbone states and inter base pair parameters, which emerges as a common theme across all the complementary dinucleotides. In sum, the global agreement between simulations and experiment reveals new aspects of intrinsic DNA mechanics, a key component of DNA-protein recognition.

Relaxation of the topological T1 process in a two-dimensional foam

The so-called topological T1 process, during which bubbles within a foam exchange neighbours is studied. The Durand and Stone model (Phys. Rev. Lett., 97, 226101 (2006)) describes the growth of a film that is newly created during the T1 process, and also the evolution of surfactant concentration on this newly created film. Here some characteristic features of the Durand and Stone model (not previously described by Durand and Stone) are elucidated. In particular it is shown that the surfactant concentration on the newly created film is predicted to undergo an extremely rapid initial evolution, which occurs long before the film itself approaches anywhere near its final equilibrium length. Associated with this, the predicted length of the newly created film tends to exhibit an extremely rapid acceleration early on in its growth. An intermediate asymptotic analysis is developed to explain the above model predictions, by focussing on the regime when the film is several times larger than its initial length, but still several times smaller than its final length. A physical explanation is offered for these predictions in terms of slippage between material points instantaneously at the end of the newly created film, and the evolving location of the film endpoint itself: this slippage implies surfactant being transferred onto the newly created film from neighbouring films, overwhelming the amount of surfactant initially present. The implications of these predictions for the likely observations in an experimental study of the T1 process are discussed.

Star-triangle equivalence in two-dimensional soap froths

In two-dimensional foams at equilibrium, triangular bubbles can be freely exchanged with threefold stars, three edges ending at a central vertex. This theorem is deduced here from Moukarzels duality. Moreover, to probe the method, a few related properties are established: under slow gas diffusion, cell extinction is a continuous process for triangles but not for other types of bubble. In general, the gas flow results in different configurations in the presence of a triangle from those in the presence of a star.

The intrinsic mechanics of B-DNA in solution characterized by NMR

Experimental characterization of the structural couplings in free B-DNA in solution has been elusive, because of subtle effects that are challenging to tackle. Here, the exploitation of the NMR measurements collected on four dodecamers containing a substantial set of dinucleotide sequences provides new, consistent correlations revealing the DNA intrinsic mechanics. The difference between two successive residual dipolar couplings (ΔRDCs) involving C6/8-H6/8, C3′-H3′ and C4′-H4′ vectors are correlated to the 31P chemical shifts (δP), which reflect the populations of the BI and BII backbone states. The δPs are also correlated to the internucleotide distances (Dinter) involving H6/8, H2′ and H2″ protons. Calculations of NMR quantities on high resolution X-ray structures and controlled models of DNA enable to interpret these couplings: the studied ΔRDCs depend mostly on roll, while Dinter are mainly sensitive to twist or slide. Overall, these relations demonstrate how δP measurements inform on key inter base parameters, in addition to probe the BI↔BII backbone equilibrium, and shed new light into coordinated motions of phosphate groups and bases in free B-DNA in solution. Inspection of the 5′ and 3′ ends of the dodecamers also supplies new information on the fraying events, otherwise neglected.

Breakdown of semi-classical conduction theory in approximants of the octagonal tiling

We present numerical calculations of quantum transport in perfect octagonal approximants. These calculations include a Boltzmann (intra-band) contribution and a non-Boltzmann (inter-band) contribution. When the unit cell size of the approximant increases, the magnitude of the Boltzmann terms decreases, whereas the magnitude of the non-Boltzmann terms increases. This shows that, in large approximants, the non-Boltzmann contributions should dominate the transport properties of electrons. This confirms the breakdown of the Bloch–Boltzmann theory for understanding the transport properties in approximants with very large unit cells, and then in quasicrystals, as found in actual Al-based approximants.

Foams in contact with solid boundaries: equilibrium conditions and conformal invariance.

Abstract.A liquid foam in contact with a solid surface forms a two-dimensional foam on the surface. We derive the equilibrium equations for this 2D foam when the solid surface is curved and smooth, generalising the standard case of flat Hele-Shaw cells. The equilibrium conditions at the vertices in 2D, at the edges in 3D, are invariant by conformal transformations. Regarding the films, conformal invariance only holds with restrictions, which we explicit for 3D and flat 2D foams. Considering foams confined in thin interstices between two non-parallel plates, normal incidence and Laplace’s law lead to an approximate equation relating the plate profile to the conformal map. Solutions are given for the logarithm and power laws in the case of constant pressure. The paper concludes on a comparison with available experimental data.