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R Lavery

Publications and source records attributed to R Lavery.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1993

Persistence analysis of the static and dynamical helix deformations of DNA oligonucleotides: application to the crystal structure and molecular dynamics simulation of d(CGCGAATTCGCG)2.

A theory and graphical presentation for the analysis of helix structure and deformations in oligonucleotides is presented. The parameters "persistence" and "flexibility" as defined in the configurational statistics of polymers of infinite length are reformulated at the oligonucleotide level in an extension of J. A. Schellman's method [(1974) Biopolymers, Vol. 17, pp. 217-226], and used as a basis for a systematic "Persistence Analysis" of the helix deformation properties for all possible subsequences in the structure. The basis for the analysis is a set of link vectors referenced to individual base pairs, and is limited to sequences exhibiting only perturbed rod-like behavior, i.e., below the threshold for supercoiling. The present application of the method is concerned with a physical model for the angular component of bending, so the link vectors are defined as the unit components of a global helix axis obtained by the procedure "Curves" of R. Lavery and H. Sklenar [(1988) J. Biomol. Struct. Dynam., Vol. 6, pp. 63-91; (1989) ibid., Vol. 6, pp. 655-667]. A discussion of the relationship between global bending and relative orientation of base pairs is provided. Our approach is illustrated by analysis of some model oligonucleotide structures with intrinsic kinks, the crystal structure of the dodecamer d(CGCGAATTCGCG)2, and the results of two molecular dynamics simulations on this dodecamer using two variations of the GROMOS force field. The results indicate that essentially all aspects of curvature in short oligonucleotides can be determined, such as the position and orientation of each bend, the sharpness or smoothness, and the location and linearity of subsequences. In the case of molecular dynamics simulations, where a Boltzmann ensemble of structures is analyzed, the spatial extent of the deformations (flexibility) is also considered.

Base Sequence↗
PubMed1993

Packing and recognition of protein structural elements: a new approach applied to the 4-helix bundle of myohemerythrin.

We present a novel search strategy for determining the optimal packing of protein secondary structure elements. The approach is based on conformational energy optimization using a predetermined set of side chain rotamers and appropriate methods for sampling the conformational space of peptide fragments having fixed backbone geometries. An application to the 4-helix bundle of myohemerythrin is presented. It is shown that the conformations of the amino acid side chains are largely determined at the level of helix pairs and that superposition of these results can be used to construct the full bundle. The final solution obtained, taking into account restrictions due to the lateral amphiphilicity of the helices, differs from the native structure by only a 20 degrees rotation of a single helix.

Amino Acid Sequence↗
PubMed1993

An analysis of the conformational paths of citrate synthase.

Previous simulation studies have provided reaction pathways leading from the closed to the open form of citrate synthase. We now undertake a detailed analysis of these pathways using a variety of different tools including backbone dihedral angles, P-Curves helicoidal parameters, inter-helix geometrical parameters, and accessibility calculations. The results point to a relatively small number of residues, mostly in loop regions, which are responsible for the majority of the conformational changes observed. An important role is attributed to transient changes in the backbone which facilitate movement along the reaction coordinate. Comparisons between the two pathways show that they share many common features despite the different algorithms used to generate them.

Algorithms↗
PubMed1993

Conformations of DNA duplexes containing 8-oxoguanine.

As a step towards elucidating the mechanisms of mutagenesis induced by irradiation and oxidation, we study the incorporation of 8-oxoguanine (OG) into duplex DNA. Molecular modelling is used to reveal changes in DNA conformational parameters due to mispairs within the sequences d(A5XA5).d(T5YT5) and d(G5XG5).d(C5YC5) where one of the bases of the bases of the central X:Y pair is OG and the other A,T,G or C. The G:C to OG:C replacements in DNA duplexes produce only minor conformational changes, similar to normal base sequence effects. The calculations suggest that both OG(syn):G and OG(syn):A mispairs can also be introduced without drastic distortion of sugar-phosphate backbone. The distortions produced by OG-containing mispairs are also found to be sequence dependent. Overall these calculations suggest that the G-->OG conversion could be an important factor in the irradiative or oxidative damage of DNA.

Algorithms↗
PubMed1992

A comprehensive classification of nucleic acid structural families based on strand direction and base pairing.

We propose a classification of DNA structures formed from 1 to 4 strands, based only on relative strand directions, base to strand orientation and base pairing geometries. This classification and its associated notation enable all nucleic acids to be grouped into structural families and bring to light possible structures which have not yet been observed experimentally. It also helps in understanding transitions between families and can assist in the design of multistrand structures.

Base Composition↗
PubMed1992

The fine structure of two DNA dodecamers containing the cAMP responsive element sequence and its inverse. Nuclear magnetic resonance and molecular simulation studies.

1H and 31P n.m.r. (nuclear magnetic resonance) spectroscopy have been used in conjunction with molecular simulation to determine the structure of two DNA dodecamers. The first of these, CATGACGTCATG, contains the octameric sequence CRE (cAMP responsive element), while the second is the reversed sequence, GTACTGCAGTAC. Structure determination was based on both NOESY (nuclear Overhauser spectroscopy) derived distances and COSY (correlated spectroscopy) dihedral angle data. Access to the 31P spectra also allowed the epsilon backbone angles to be determined. Considerable care was taken in deriving structural parameters from the n.m.r. data and an excellent level of agreement is obtained with the simulated conformations. Both dodecamers are found to belong to the B-DNA family; however, there is a striking difference between the CRE sequence and its inverse, the former conformation alone showing a strong structural heterogeneity.

Base Sequence↗
PubMed1992

Conformational sub-states in B-DNA.

Theoretical studies of the sequence-dependent conformation of B-DNA have been carried out using Jumna, a helicoidal co-ordinate minimization algorithm. The results obtained for a series of six oligomers with repetitive sequences show that, with the exception of the homopolymers (dA)n.(dT)n and (dG)n.(dC)n, all sequences can adopt a variety of conformations characterized by considerable changes in helicoidal parameters and also in sugar puckers which adopt C(2')-endo (falling into 2 classes) or, in the case of pyrimidine nucleotides, O(1')-endo forms. These studies lead to an improved understanding of the role of base sequence on DNA conformation and point to a number of interesting correlations between the various structural parameters describing the double helix.

Algorithms↗
PubMed1992

DNA flexibility as a function of allomorphic conformation and of base sequence.

Systematic theoretical modeling of symmetric DNA oligomers, carried out earlier for the B conformation, is now extended to A-DNA. In contrast to the previous results, it is found that A-DNA shows no multiplicity of low-energy substate conformations. The possibilities of the Jumna algorithm are subsequently applied to studying deformations of the oligomers. Controlled winding and stretching deformations are used to study how the two allomorphs and different base sequences absorb such external stress. The results help explain the internal mechanics of the DNA double helix and the extent to which fine structure influences this behavior. The results point to some differences between the A and B double helices, but also to many similarities. Sequence effects on flexibility are relatively limited compared to their impact on optimal energy conformations. It is also shown that the conformational substates detected for B-DNA oligomers are preserved under deformation, but have little influence on its energetics.

Base Sequence↗
PubMed1992

Strand orientation of [alpha]-oligodeoxynucleotides in triple helix structures: dependence on nucleotide sequence.

The aims of the present theoretical study of the conformations of [alpha]-oligodeoxynucleotides forming triple helices with DNA duplexes are to understand the structural and energetic factors involved in [alpha]-triple helix formation by means of energy minimization, and to explain the experimentally observed dependence of strand orientation on the nucleotide sequence. It is found that the energetically preferred orientation of the [alpha]-oligonucleotide with respect to the homopurine strand depends on the sequence of the homopurine.homopyrimidine tracts. This is a consequence of the structural heteromorphism of base triplets in the intrinsically more stable reverse Hoogsteen hydrogen bonding configuration. Practical rules are proposed for determining the orientation of the nuclease-resistant [alpha]-oligodeoxynucleotide strand which will form the most stable triple helix.

Base Sequence↗
PubMed1992

A computational and experimental study of the bending induced at a double-triple helix junction.

We have studied the conformation of a 17 base-pair homopyrimidine.homopurine triple helix formed on a fragment of duplex DNA derived from Simian Virus SV40. Gel retardation assays indicate that an 80 base-pair fragment has an altered conformation when the triple helix is formed, which is most likely to result from an induced bend in the DNA. Investigation of the detailed conformation of the double helix-triple helix junctions has been performed by means of molecular modelling. Bending on the 5' and 3' sides of the third strand oligonucleotide are not located at equivalent positions with respect to the junctions, which is explained in terms of base stacking. The junction effects on DNA structure, induced by the requirement for cytosine protonation in the Hoogsteen-bonded strand to form CGC+ base triplets, are also discussed.

Base Sequence↗
PubMed1991

A new approach to the rapid determination of protein side chain conformations.

Two efficient algorithms have been developed which allow amino acid side chain conformations to be optimized rapidly for a given peptide backbone conformation. Both these approaches are based on the assumption that each side chain can be represented by a small number of rotameric states. These states have been obtained by a dynamic cluster analysis of a large data base of known crystallographic structures. Successful applications of these algorithms to the prediction of known protein conformations are presented.

Algorithms↗
PubMed1991

Triple helix structures: sequence dependence, flexibility and mismatch effects.

By means of molecular modelling, electrostatic interactions are shown to play an important role in the sequence-dependent structure of triple helices formed by a homopyrimidine oligonucleotide bound to a homopurine. homopyrimidine sequence on DNA. This is caused by the presence of positive charges due to the protonation of cytosines in the Hoogsteen-bonded strand, required in order to form C.GxC+ triplets. Energetic and conformational characteristics of triple helices with different sequences are analyzed and discussed. The effects of duplex mismatches on the triple helix stability are investigated via thermal dissociation using UV absorption.

Base Sequence↗
PubMed1991

Theoretical study of ethidium intercalation in triple-stranded DNA and at triplex-duplex junctions.

The contribution of different factors in the interaction of ethidium intercalated into various sequences of a triple helix, or in the region of the junction between the double- and triple-stranded DNA has been studied by energy minimization. It is found that in the total energy of the ethidium- triple helix complexes, a particular electrostatic contribution emerges due to the presence of protonated cytosines in the triple helix. This parameters is determinant in the sequence-specificity of ethidium binding to the triple helix. The preferred intercalation sites of ethidium in the triple helix are proposed. The interaction of ethidium at the triplex-duplex junction, and its effects are also discussed. This study is aimed at searching for new drugs specific for the triple helix, or for the triplex-duplex junctions.

Base Sequence↗
PubMed1990

Conformational and helicoidal analysis of the molecular dynamics of proteins: "curves," dials and windows for a 50 psec dynamic trajectory of BPTI.

A new procedure for the graphic analysis of molecular dynamics (MD) simulations on proteins is introduced, in which comprehensive visualization of results and pattern recognition is greatly facilitated. The method involves determining the conformational and helicoidal parameters for each structure entering the analysis via the method "Curves," developed for proteins by Sklenar, Etchebest, and Lavery (Proteins: Structure, Function Genet. 6:46-60, 1989) followed by a novel computer graphic display of the results. The graphic display is organized systematically using conformation wheels ("dials") for each torsional parameter and "windows" on the range values assumed by the linear and angular helicoidal parameters, and is present in a form isomorphous with the primary structure per se. The complete time evolution of dynamic structure can then be depicted in a set of four composite figures. Dynamic aspects of secondary and tertiary structure are also provided. The procedure is illustrated with an analysis of a 50 psec in vacuo simulation on the 58 residue protein, bovine pancreatic trypsin inhibitor (BPTI), in the vicinity of the local minimum on the energy surface corresponding to a high resolution crystal structure. The time evolution of 272 conformational and 788 helicoidal parameters for BPTI is analyzed. A number of interesting features can be discerned in the analysis, including the dynamic range of conformational and helicoidal motions, the dynamic extent of 2 degrees structure motifs, and the calculated fluctuations in the helix axis. This approach is expected to be useful for a critical analysis of the effects of various assumptions about force field parameters, truncation of potentials, solvation, and electrostatic effects, and can thus contribute to the development of more reliable simulation protocols for proteins. Extensions of the analysis to present differential changes in conformational and helicoidal parameters is expected to be valuable in MD studies of protein complexes with substrates, inhibitors, and effectors and in determining the nature of structural changes in protein-protein interactions.

Biological Evolution↗