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R Lavery

Publications and source records attributed to R Lavery.

At least 37 records · Page 2Linked to original sources
PubMed1998

A model for parallel triple helix formation by RecA: single-single association with a homologous duplex via the minor groove.

The nucleoproteic filaments of RecA polymerized on single stranded DNA are able to integrate double stranded DNA in a coaxial arrangement (with DNA stretched by a factor 1.5), to recognize homologous sequences in the duplex and to perform strand exchange between the single stranded and double stranded molecules. While experimental results favor the hypothesis of an invasion of the minor groove of the duplex by the single strand, parallel minor groove triple helices have never been isolated or even modeled, the minor groove offering little space for a third strand to interact. Based on an internal coordinate modeling study, we show here that such a structure is perfectly conceivable when the two interacting oligomers are stretched by a factor 1.5, in order to open the minor groove of the duplex. The model helix presents characteristics that coincide with known experimental data on unwinding, base pair inclination and inter-proton distances. Moreover, we show that extension and unwinding stabilize the triple helix. New patterns of triplet interaction via the minor groove are presented.

Computer Simulation↗
PubMed1998

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.

Computer Simulation↗
PubMed1997

Local DNA stretching mimics the distortion caused by the TATA box-binding protein.

X-ray structures of the TATA box-binding protein complexed with its DNA target show that the nucleic acid is severely bent away from the protein and also strongly unwound. We have used molecular mechanics and energy mapping to understand how such an unusual conformation can be induced. The results show that simple deformation pathways involving local stretching or unwinding of DNA reproduce many features of the experimental structure. Notably, kinked junctions with the flanking B-DNA regions occur without the need for any specific local

DNA↗
PubMed1997

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.

DNA↗
PubMed1997

Distortions of the DNA double helix induced by 1,3-trans-diamminedichloroplatinum(II)-intrastrand cross-link: an internal coordinate molecular modeling study.

A trans-diamminedichloroplatinum(II) (trans-DDP) intrastrand adduct within the sequence d(TCTG*TG*TC).d(GACACAGA) (where G* represents a platinated guanine) is modeled on the basis of qualitative experimental data concerning global unwinding and curvature as well as information on base pairing. Modeling is performed using the internal coordinate JUMNA program, specific to nucleic acids, and modified to include the possibility of covalently bound ligands. Calibration of the energy functions representing the Pt-N7 bond with guanine is described. The platinum atom and the platinum-nitrogen bonds are parameterized for use in the Hückel Del Re method to calculate monopoles at each atom. These monopoles are consistent with the Flex force field included in Jumna. By developing an appropriate minimization protocol we are able to generate stable, distorted three-dimensional structures compatible with the experimental data and including an unusually high global unwinding. No a priori geometric assumptions are made in generating these structures.

Algorithms↗
PubMed1997

Conformational properties of the TATA-box binding sequence of DNA.

Nanosecond scale molecular dynamics simulations in water demonstrate that the DNA oligomer, GCGTATATAAAACGC, which contains a target site for the TATA-box binding protein (TBP), has an intrinsic preference to adopt an A-like conformation in the region of the TATA-box and undergoes bending related to that seen within in the TBP complex. This result is obtained from two independent simulations using different starting structures. In line with earlier suggestions of Guzikevich-Guerstein and Shakked, these simulations imply that an A-DNA conformation may be an important intermediate step in forming the strongly distorted DNA observed within the crystallographically determined complex with TBP. These results also support modeling studies by Lebrun et al. which suggest that the TBP binding mechanism can be broken down into a backbone transition to an A-like form coupled with a mechanical distortion which locally stretches and unwinds the DNA.

Binding Sites↗
PubMed1996

Modelling extreme stretching of DNA.

Molecular modelling with Jumna is used to study extreme stretching of the DNA double helix. The results, which correlate well with recent nanomanipulation experiments, show how the double helix can be extended to twice its normal length before its base pairs break. Depending on the way the duplex is stretched two types of conformation can occur, either an unwound flat ribbon or a narrow fibre with negatively inclined base pairs. The energetics of both types of deformation are similar and existing structures show that at least the flat ribbon form can exist locally under biological conditions.

Base Sequence↗
PubMed1996

Molecular modelling of (A4T4NN)n and (T4A4NN)n: sequence elements responsible for curvature.

The molecular modelling program JUMNA has been used to investigate the origins of the strikingly different curvature of the two sequences, (A4T4NN)n and (T4A4NN)n. Gel electrophoresis and cyclisation studies have shown that only the former of these two sequences is significantly curved. By developing novel superhelical symmetry constraints we were able to study the energetic and structural aspects of polymeric DNA having a controlled curvature. The results obtained (which do not take into account specific hydration effects) correlate well with the experimental data and offer a molecular level explanation of curvature. Although curvature is found to be initiated by specific dinucleotide junctions, deformations spread to surrounding dinucleotide steps and, moreover, sequence effects beyond the dinucleotide level are observed.

Base Sequence↗
PubMed1996

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.

Chemical Phenomena↗
PubMed1995

Low-frequency vibrations in alpha-helices: helicoidal analysis of polyalanine and deoxymyoglobin molecular dynamics trajectories.

We present an approach to the analysis of low-frequency (0-200 cm-1) alpha-helix vibrations in molecular dynamics simulations. The approach employs the P-Curves algorithm [H. Sklenar, C. Etchebest, and R. Lavery, (1989) Proteins: Structure, Function and Genetics, Vol. 6, pp. 46-60] to determine the helical axis and a set of helicoidal parameters describing the axis curvature and the position of the repeating units with respect to the axis and each other. The vibrations are analyzed in terms of time correlation functions of the fluctuations of P-Curves parameters and their Fourier transforms. Simulations of polyalanine and myoglobin are analyzed. For polyalanine, global twisting, bending, and stretching vibrations are found at 11, 20, and 40 cm-1, respectively. In myoglobin, the spectra of the global helix vibrations are qualitatively different from those of polyalanine and considerably more complicated. Local vibrations of individual amino acid units in the helix backbones are also analyzed with P-Curves and compared.

Algorithms↗
PubMed1995

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 (SET's) 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.

DNA↗
PubMed1994

Theoretical studies of DNA-RNA hybrid conformations.

Molecular modelling has been used to probe the conformational preferences of double stranded DNA-RNA hybrids. As might be expected, the sugars of the DNA strand have higher conformational flexibility, but, for the majority of the repetitive sequences studied, these sugars prefer a C2-endo pucker, while ribose sugars uniformly adopt a C3-endo pucker. This gives rise to a strongly heteronomous duplex conformation. One exception to this rule involves the thymidine strand of poly(dT).poly(rA), which marginally prefers a C3-endo pucker. Our study further indicates that the DNA strands of the hybrids favour backbone torsions in the canonical B domain, rather than the modified values proposed on the basis of fibre diffraction studies. Backbone conformational transitions can nevertheless be induced leading to an alpha gamma-flip (alpha:gamma, g-/g(+)-->t/t) or to the alpha beta gamma-flip form proposed from fibre studies (alpha:beta:gamma, g-/t/g(+)-->t/g+/t). The latter transition is also found to be linked to BI-->BII transitions (epsilon:zeta, t/g(-)-->g-/t).

Algorithms↗
PubMed1994

Prediction of the positioning of the seven transmembrane alpha-helices of bacteriorhodopsin. A molecular simulation study.

We have applied a search strategy for determining the optimal packing of protein secondary structure elements to the rotational positioning of the seven transmembrane helices of bacteriorhodopsin. The search is based on the assumption that the relative orientations of the helices within the bundle are conditioned principally by inter-helix side-chain interactions and that the extra-helical parts of the protein have only a minor influence on the bundle conformation. Our approach performs conformational energy optimization using a predetermined set of side-chain rotamers and appropriate methods for sampling the conformational space of peptide fragments with fixed backbone geometries. The final solution obtained for bacteriorhodopsin places each of the seven helices to a precision of a few degrees in rotation around the helical axis and to a few tenths of an ångström in translation along the helical axis with respect to the best experimental structure obtained by electron diffraction, except for helix D, where our results support the suggestion that this helix should be displaced along its axis toward its N terminus. The perspectives of such an approach for the determination of the structures of other transmembrane helical bundles are discussed.

Bacteriorhodopsins↗
PubMed1994

Measuring the geometry of DNA grooves.

We present a new method for measuring the widths and depths of the grooves formed within DNA helices. This method overcomes the limitations of simply measuring interstrand phosphate-phosphate distances and has the advantage of yielding continuous values for groove geometry along a DNA fragment. In the case of oligonucleotides, it also clearly indicates the zones in which grooves exist, bounded by two phosphodiester backbones. The methodology has been developed within the Curves algorithm for studying irregular DNA geometries and is based on the optimal, and generally curved, helical axis obtained by this analysis.

Algorithms↗
PubMed1994

Modelling DNA conformational mechanics.

Using a modelling technique specifically adapted to DNA helices, we have systematically studied the impact of base sequence on the geometry of the double helix. The results obtained show that each repetitive base sequence leads to several stable conformations belonging to the B-DNA family. These conformational sub-states generally have similar stabilities, but often differ considerably in terms of their helical and backbone parameters. Each sub-state can be characterised by the puckering of its sugar rings. Surface energy mapping and combinatorial search techniques are used to further understand the DNA conformational hypersurface and to extend our study from dinucleotide repeats to tetranucleotide sequences. The resulting structural database should be useful for predicting the properties of longer and more irregular base sequences and thus should contribute to understanding how DNA target sites are recognised.

Base Sequence↗
PubMed1993

A possible family of B-like triple helix structures: comparison with the Arnott A-like triple helix.

Recent experimental studies of the structure of triple helices show that their conformation in solution differs from the A-like structure derived from diffraction data on triple helix fibers by Arnott and co-workers. Here we show by means of molecular modeling that a family of triple helix structures may exist with similar conformational energies, but with a variety of sugar puckers. The characteristics of these putative triple helices are analyzed for three different base sequences: (T.AxT)n, (C.GxC+)n, and alternating (C.GxC+/T.AxT)n. In the case of (C.GxC+)n triple helix, infrared and Raman spectra have been obtained and clearly reveal the existence of both N- and S-type sugars in solution. The molecular mechanics calculations allow us to propose a stereochemically reasonable model for this triple helix, in good agreement with the vibrational spectroscopy results.

Algorithms↗
PubMed1993

BI-BII transitions in B-DNA.

Molecular modelling is used to study the conformational and energetic aspects of BI-BII transitions within the backbone of a B-DNA dodecamer d(CATGACGTCATG) whose fine structure has previously been determined by molecular modelling combined with NMR spectroscopy. It is shown that while the dodecamer under investigation does not contain any BII junctions, the central CpG step can most easily undergo the transition. More generally, it is also found that the base sequence and hence the backbone geometry of a DNA segment, strongly influences both the conformational impact of the transition, the associated energy barrier and the stability of the resulting BII state.

Base Sequence↗