Anne Lebrun

DNA: An Extensible Molecule

The force-displacement response of a single duplex DNA molecule was measured. The force saturates at a plateau around 70 piconewtons, which ends when the DNA has been stretched about 1.7 times its contour length. This behavior reveals a highly cooperative transition to a state here termed S-DNA. Addition of an intercalator suppresses this transition. Molecular modeling of the process also yields a force plateau and suggests a structure for the extended form. These results may shed light on biological processes involving DNA extension and open the route for mechanical studies on individual molecules in a previously unexplored range.

Structure and mechanics of single biomolecules: experiment and simulation

One of the main goals of molecular biology is to understand the structure of biomolecules. With the emergence of single molecule manipulation techniques that structure can now be controlled by the application of stretching and torsional stresses. In this article we review some recent experiments on the stretching and twisting of single biopolymers, testing the elastic properties of DNA and proteins and studying their stress-induced structural transitions. Numerical simulations have emerged as a precious tool to interpret the experimental data and predict the associated structural changes. We shall explain how a combination of these experimental and computational tools open a new vista on the structure of biomolecules.

Unusual DNA conformations

DNA is on the move across conformational space. Duplexes diversity and, joined by triplexes, quadruplexes, loops, bulges and multiarmed junctions, open the route to a bewildering array of increasingly complex conformations. In addition to this structural growth, DNA has come under increasing scrutiny thanks to the development of chemical and physical techniques for deforming its conformation and probing its properties. These investigations help us to learn more about the mechanics and the activity of this remarkably versatile macromolecule.

Modelling DNA stretching for physics and biology

We have used internal coordinate molecular mechanics calculations to study how the DNA double helix deforms upon stretching. Results obtained for polymeric DNA under helical symmetry constraints suggest that two distinct forms, an unwound ribbon and a narrow fibre, can be formed as a function of which ends of the duplex are pulled. Similar results are also obtained with DNA oligomers. These experiments lead to force curves which exhibit a plateau as the conformational transition occurs. This behaviour is confirmed by applying an increasing force to DNA and observing a sudden length increase at a critical force value. It is finally shown some DNA binding proteins can also stretch DNA locally, to conformations related to those created by nanomanipulation.

Modeling the Mechanics of a DNA Oligomer

DNA stretching and strand separation have been studied by molecular mechanics using an oligomer which has been the subject of nanomanipulation experiments (Noy et al., Chem. Biol. 4, 519, 1997). Adiabatic mapping of conformational energy carried out as a function of stretching leads to force/extension curves in good correlation with the experimental results. Other types of deformation are also modeled and compared with the experimental results obtained on polymeric DNA. The results highlight overall similarities, but point to thermodynamic differences and also to local base sequence effects which can be expected to play an important role at the level of biologically induced structural deformations.

MODELING A STRAND EXCHANGE TETRAPLEX CONFORMATION

Molecular modeling had been used to study the conformation and the energetics of 4-stranded DNA complexes formed by strand exchange between two duplexes. Both isolated strand exchange tetraplexes (SETs) and duplex-tetraplex complexes are found to be stable. Hydrogen bonding between the major groove faces of the base pairs within each base tetrad is shown to be specific, allowing tetrad formation only between DNA duplexes having identical base sequences. Such structures can explain the recent experimental observations of Gaillard and Strauss concerning the complexation of two DNA containing poly(dCA) tracts and may be of relevance to genetic recombination mechanisms.