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PubMed2004

Discrimination between BI and BII conformational substates of B-DNA based on sugar-base interproton distances.

Molecular dynamics (MD) simulations of four water-solvated DNA duplexes were used to generate a database of approximately 27000 dinucleotide conformations. Analyzing this database, we investigated the relationship between so-called BI-BII transitions and short-range interproton distances. Four H-H distances were found particularly sensitive to BI-BII transitions: internucleotide H1'(n)-H68(n+1), H2'(n)-H68(n+1), and H2"(n)-H68(n+1), and intranucleotide H2"(n)-H68(n). Determination of these distances using classical NOESY spectroscopy can thus provide valuable indications on the existence of BII substates, complementing the existing method based on (31)P chemical shifts and (31)P-(1)H spin-spin coupling constants.

Computer Simulation↗
PubMed2004

Solvent interactions and protein dynamics in spin-labeled T4 lysozyme.

Aspects of T4 lysozyme dynamics and solvent interaction are investigated using atomically detailed Molecular Dynamics (MD) simulations. Two spin-labeled mutants of T4 lysozyme are analyzed (T4L-N40C and T4L-K48C), which have been found from electronic paramagnetic resonance (EPR) experiments to exhibit different mobilities at the site of spin probe attachment (N- and C-terminus of helix B, respectively). Similarities and differences in solvent distribution and diffusion around the spin label, as well as around exposed and buried residues within the protein, are discussed. The purpose is to capture possible strong interactions between the spin label (ring) and solvent molecules, which may affect EPR lineshapes. The effect of backbone motions on the water density profiles is also investigated. The focus is on the domain closure associated with the T4 lysozyme hinge-bending motion, which is analyzed by Essential Dynamics (ED). The N-terminus of helix B is found to be a "hinge" residue, which explains the high degree of flexibility and motional freedom at this site.

Bacteriophage T4↗
PubMed2005

The protein-protein interactions between SMPI and thermolysin studied by molecular dynamics and MM/PBSA calculations.

Thermolysin is a zinc-metalloendopeptidase secreted by the gram-positive thermophilic bacterium Bacillus thermoproteolyticus. Thermolysin belongs to the gluzinicin family of enzymes, which is selectively inhibited by Steptomyces metalloproteinase inhibitor (SMPI). Very little is known about the interaction between SMPI and thermolysin. Knowledge about the protein-protein interactions is very important for designing new thermolysin inhibitors with possible industrial or pharmaceutical applications. In the present study, two binding modes between SMPI and thermolysin were studied by 2300 picoseconds (ps) of comparative molecular dynamics (MD) simulations and calculation of the free energy of binding using the molecular mechanics-Poisson-Boltmann surface area (MM/PBSA) method. One of the positions, the 'horizontal arrow head docking' (HAHD) was similar to the previously proposed binding mode by Tate et al. (Tate, S., Ohno, A., Seeram, S. S., Hiraga, K., Oda, K., and Kainosho, M. J. Mol. Biol. 282, 435-446 (1998)). The other position, the 'vertical arrow head docking' (VAHD) was obtained by a manual docking guided by the shape and charge distribution of SMPI and the binding pocket of thermolysin. The calculations showed that SMPI had stronger interactions with thermolysin in the VAHD than in the HAHD complex, and the VAHD complex was considered more realistic than the HAHD complex. SMPI interacted with thermolysin not only at the active site but had auxiliary binding sites contributing to proper interactions. The VAHD complex can be used for designing small molecule inhibitors mimicking the SMPI-thermolysin binding interfaces.

Bacillus↗
PubMed2005

Dynamics of the native and the ligand-bound structures of eosinophil cationic protein: network of hydrogen bonds at the catalytic site.

Eosinophil Cationic Protein (ECP) is sequentially and structurally similar to ribonuclease A (RNase A). It belongs to the RNase A family of proteins and the RNA catalysis is essential to its biological function. In the present study, we have generated the dinucleotide-bound structures of ECP by docking the dinucleotides to a number of molecular dynamics (MD) generated ECP structures. The stability of the docked enzyme-ligand complexes was ascertained by extensive MD simulations. The modes of ligand binding are explored by essential dynamics studies. The role of water molecules in the stability of the complex and in the catalysis was investigated. The active site residues form a complex network of connections with the ligand and with a water molecule. The catalytic mechanism of the RNA cleavage is examined on the basis of the active site geometry obtained by the simulations.

Binding Sites↗
PubMed2005

Oxetane locked thymidine in the Dickerson-Drew dodecamer causes local base pairing distortions -- an NMR structure and hydration study.

The introduction of a North-type sugar conformation constrained oxetane T block, 1-(1',3'-O-anhydro-beta-D-psicofuranosyl) thymine, at the T(7) position of the self-complementary Dickerson-Drew dodecamer, d[(5'-C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12)-3')](2), considerably perturbs the conformation of the four central base pairs, reducing the stability of the structure. UV spectroscopy and 1D NMR display a drop in melting temperature of approximately 10 degrees C per modification for the T(7) oxetane modified duplex, where the T(7) block has been introduced in both strands, compared to the native Dickerson-Drew dodecamer. The three dimensional structure has been determined by NMR spectroscopy and has subsequently been compared with the results of 2.4 ns MD simulations of the native and the T(7) oxetane modified duplexes. The modified T(7) residue is found to maintain its constrained sugar- and the related glycosyl torsion conformations in the duplex, resulting in staggered and stretched T(7).A(6) and A(6).T(7) non-linear base pairs. The stacking is less perturbed, but there is an increased roll between the two central residues compared to the native counterpart, which is compensated by tilts of the neighboring base steps. The one dimensional melting profile of base protons of the T(7) and T(8) residues reveals that the introduction of the North-type sugar constrained thymine destabilizes the core of the modified duplex, promoting melting to start simultaneously from the center as well as from the ends. Temperature dependent hydration studies by NMR demonstrate that the central T(7).A(6)/A(6).T(7) base pairs of the T(7) oxetane modified Dickerson-Drew dodecamer have at least one order of magnitude higher water exchange rates (correlated to the opening rate of the base pair) than the corresponding base pairs in the native duplex.

Base Composition↗
PubMed2005

Long-range electrostatic interactions in molecular dynamics: an endothelin-1 case study.

An extensive conformational search in explicit solvent was performed in order to compare the influence of different long-range electrostatic interaction treatments in molecular dynamics. The short peptide endothelin-1 was selected as the subject of molecular dynamics studies that started from both X-ray and NMR obtained structures. Electrostatic interactions were treated using two of the most common methods--residue-based cutoff and particle mesh Ewald (PME). Analyses of free energy calculations (MM-PBSA method used), secondary structure elements and hydrogen bonds were performed, and there suggested that there is no unambiguous conclusion about which of the two methods of long-range electrostatics treatment should be used in MD simulations in this case. The most reliable data was provided by a trajectory that started with the NMR structure and used the cutoff method to treat electrostatic interactions. This leads to a recommendation that the choice of electrostatics treatment should be made carefully and not automatically by choosing the PME method simply because it is the most widely used.

Endothelin-1↗
PubMedDate not supplied

Fluorescent alpha-anomeric 1,N(6)etheno-deoxyadenosine in DNA duplexes. The alpha-epsilondA / dG pair.

Structural properties of the fluorescent alpha-anomeric 1,N(6)ethenodeoxyadenosine residue placed in opposition to all four canonical deoxynucleotide units within 11-mer DNA duplexes have been studied. The duplex with alpha-epsilondA / dG pairing is most thermodynamically stable while the alpha-epsilondA / dC one is the least stable. Fluorescence measurements confirm the thermodynamic data and indicate base-pair dependent stacking properties of alpha-epsilondA within duplex structures. Results of molecular dynamics (MD) simulations in aqueous solution for the most stable duplex point to the presence of different conformational states of the alpha-1,N(6)etheno-deoxyadenosine residue, including formation of a hydrogen bonded pair with the dG and possible occurrence of severe kinking in the duplex.

Base Sequence↗
PubMed2005

Synthesis of spin-labeled RNAs for long range distance measurements by peldor.

Site directed spin labeled RNA duplexes with different interspin distances were synthesized. The radical 2,2,5,5-tetramethyl-pyrrolin- 1-yloxyl-3-acetylene (TPA) was introduced during the solid-phase synthesis through a Sonogashira cross-coupling with 5-iodo-uridine. Tm and CD studies showed that the spin label does not to disturb significantly the A-form of these duplexes. 4-Pulse Electron Double Resonance (PELDOR) was then used to measure intramolecular spin-spin distances of 19.3, 33.0 and 40.9 A, which are in very good agreement with the calculated values of 17.6, 32.1 and 39.1 A, obtained from Molecular Dynamics (MD) simulations.

Biochemistry↗
PubMed2004

Side chain interactions determine the amyloid organization: a single layer beta-sheet molecular structure of the calcitonin peptide segment 15-19.

In this paper we present a detailed atomic model for a protofilament, the most basic organization level, of the amyloid fibre formed by the peptide DFNKF. This pentapeptide is a segment derived from the human calcitonin, a natural amyloidogenic protein. Our model, which represents the outcome of extensive explicit solvent molecular dynamics (MD) simulations of different strand/sheet organizations, is a single beta-sheet filament largely without a hydrophobic core. Nevertheless, this structure is capable of reproducing the main features of the characteristic amyloid fibril organization and provides clues to the molecular basis of its experimental aggregation behaviour. Our results show that the side chains' chemical diversity induces the formation of a complex network of interactions that finally determine the microscopic arrangement of the strands at the protofilament level. This network of interactions, consisting of both side chain-side chain and backbone-side chain interactions, confers on the final single beta-sheet arrangement an unexpected stability, both by enhancing the association of related chemical groups and, at the same time, by shielding the hydrophobic segments from the polar solvent. The chemical physical characterization of this protofilament provides hints to the possible thermodynamical basis of the supra molecular organization that allows the formation of the filaments by lateral association of the preformed protofibrils. Its regular, highly polarized structure shows how other protofilaments can assemble. In terms of structural biology, our results clearly indicate that an amyloid organization implies a degree of complexity far beyond a simple nonspecific association of peptide strands via amide hydrogen bonds.

Amino Acid Sequence↗
PubMed2006

Structural bioinformatics of DNA: a web-based tool for the analysis of molecular dynamics results and structure prediction.

UNLABELLED: We report here the release of a web-based tool (MDDNA) to study and model the fine structural details of DNA on the basis of data extracted from a set of molecular dynamics (MD) trajectories of DNA sequences involving all the unique tetranucleotides. The dynamic web interface can be employed to analyze the first neighbor sequence context effects on the 10 unique dinucleotide steps of DNA. Functionality is included to build all atom models of any user-defined sequence based on the MD results. The backend of this interface is a relational database storing the conformational details of DNA obtained in 39 different MD simulation trajectories comprising all the 136 unique tetranucleotide steps. Examples of the use of this data to predict DNA structures are included. AVAILABILITY: http://humphry.chem.wesleyan.edu:8080/MDDNA. SUPPLEMENTARY INFORMATION: Supplementary data including color figures are available at Bioinformatics online.

Base Sequence↗
PubMed2004

Bare-faced curassow lysozyme carrying amino acid substitutions at subsites E and F shows a change in activity against chitooligosaccharide caused by a local conformational change.

A new form of avian lysozyme, bare-faced curassow lysozyme (BCL), was purified and chemically sequenced. Of the 26 substitutions relative to chicken lysozyme, three, F34Y, T47S, and R114H, are of substrate-interacting residues in the E and F subsites, which would contribute to the acceptor binding for transglycosylation. T47S is a novel substitution in this lysozyme class. While other lysozymes also have substitutions at positions 114 and 34, they also contain numerous others, including ones in the other substrate binding sites, A-D. Furthermore, T47S lies on the left side, while F34Y and R114H are located on the right side of the E-F subsites. BCL therefore should allow comparison of the independent contributions of these sites to substrate binding and transglycosylation. The activity toward the N-acetylglucosamine pentamer revealed that the substitutions at the E-F sites reduced the binding free energies at the E-F sites and the rate constant for transglycosylation without the conformation change of other substrate binding sites on the protein. MD simulation analysis of BCL suggested that the substituted amino acids changed the local conformation of this lysozyme at the E-F sites.

Acetylglucosamine↗
PubMed1996

Efficient triple helix formation by oligodeoxyribonucleotides containing alpha- or beta-2-amino-5-(2-deoxy-D-ribofuranosyl) pyridine residues.

Triple helices containing C+xGxC triplets are destabilised at physiological pH due to the requirement for base protonation of 2'-deoxycytidine (dC), which has a pKa of 4.3. The C nucleoside 2-amino-5-(2'-deoxy-beta-D-ribofuranosyl)pyridine (beta-AP) is structurally analogous to dC but is considerably more basic, with a pKa of 5.93. We have synthesised 5'-psoralen linked oligodeoxyribonucleotides (ODNs) containing thymidine (dT) and either beta-AP or its alpha-anomer (alpha-AP) and have assessed their ability to form triplexes with a double-stranded target derived from standard deoxynucleotides (i.e. beta-anomers). Third strand ODNs derived from dT and beta-AP were found to have considerably higher binding affinities for the target than the corresponding ODNs derived from dT and either dC or 5-methyl-2'-deoxycytidine (5-Me-dC). ODNs containing dT and alpha-AP also showed enhanced triplex formation with the duplex target and, in addition are more stable in serum-containing medium than standard oligopyrimidine-derived ODNs or ODNs derived from dT and beta-AP. Molecular modelling studies showed that an alpha-anomeric AP nucleotide can be accommodated within an otherwise beta-anomeric triplex with only minor perturbation of the triplex structure. Molecular dynamics (MD) simulations on triplexes containing either the alpha- or beta-anomer of (N1-protonated) AP showed that in both cases the base retained two standard hydrogen bonds to its associated guanine when the 'A-type' model of the triplex was used as the start-point for the simulation, but that bifurcated hydrogen bonds resulted when the alternative 'B-type' triplex model was used. The lack of a differential stability between alpha-AP- and beta-AP-containing triplexes at pH >7, predicted from the behaviour of the B-type models, suggests that the A-type models are more appropriate.

Electrophoresis, Polyacrylamide Gel↗
PubMed1997

Solution structure of RNA duplexes containing alternating CG base pairs: NMR study of r(CGCGCG)2 and 2'-O-Me(CGCGCG)2 under low salt conditions.

Structures of r(CGCGCG)2 and 2'-O-Me(CGCGCG)2 have been determined by NMR spectroscopy under low salt conditions. All protons and phosphorus nuclei resonances have been assigned. Signals of H5'/5" have been assigned stereospecifically. All 3JH,H and 3JP,H coupling constants have been measured. The structures were determined and refined using an iterative relaxation matrix procedure (IRMA) and the restrained MD simulation. Both duplexes form half-turn, right-handed helices with several conformational features which deviate significantly from a canonical A-RNA structure. Duplexes are characterised as having C3'-endo sugar pucker, very low base-pair rise and high helical twist and inclination angles. Helices are overwound with <10 bp per turn. There is limited inter-strand guanine stacking for CG steps. Within CG steps of both duplexes, the planes of the inter-strand cytosines are not parallel while guanines are almost parallel. For the GC steps this pattern is reversed. The 2'-O-methyl groups are spatially close to the 5'-hydrogens of neighbouring residues from the 3'-side and are directed towards the minor groove of 2'-O-Me(CGCGCG)2 forming a hydrophobic layer. Solution structures of both duplexes are similar; the effect of 2'-O-methylation on the parent RNA structure is small. This suggests that intrinsic properties imposed by alternating CG base pairs govern the overall conformation of both duplexes.

Base Composition↗
PubMed2001

Impact of CpG methylation on structure, dynamics and solvation of cAMP DNA responsive element.

Methylation of CpG motifs in DNA is involved in the control of gene expression and in several other epigenic effects. It suppresses also the immuno-stimulation properties of bacterial or viral DNAs that contain CPGS: However, effects of methylation on the DNA structure and dynamics are not clear. Here we carried out a 10 ns MD simulation, confronted to an NMR analysis, of a hexadecanucleotide with the cAMP responsive element (CRE) DNA methylated at its center: d(GAGATGAmCGTCATCTC)(2) (CREmet). Methylation does not introduce significant structure modification but reduces the dynamics. Molecular mechanics and generalized Born solvation energy calculations showed that the stiffness of CREmet arises from both a restriction of the conformational space by the bulky methyl groups and a folding of DNA around the hydrophobic methyls. The latter effect is favored when the GpA steps belonging to the TGA binding half-sites adopt the BII conformation. The inability of the methylated DNAs to interact with their protein partners-either transcription factors for gene regulation or a Toll-like receptor for immunostimulation-could result from both the obstacle created by methyls, preventing crucial interactions, and the loss of DNA flexibility, reducing its adaptability. Results are discussed in the light of NMR and crystallographic data.

Base Sequence↗
PubMed2003

Altered structural fluctuations in duplex RNA versus DNA: a conformational switch involving base pair opening.

DNA and RNA are known to have different structural properties. In the present study, molecular dynamics (MD) simulations on a series of RNA and DNA duplexes indicate differential structural flexibility for the two classes of oligonucleotides. In duplex RNA, multiple base pairs experienced local opening events into the major groove on the nanosecond time scale, while such events were not observed in the DNA simulations. Three factors are indicated to be responsible for the base opening events in RNA: solvent-base interactions, 2'OH(n)-O4'(n+1) intra-strand hydrogen bonding, and enhanced rigid body motion of RNA at the nucleoside level. Water molecules in the major groove of RNA contribute to initiation of base pair opening. Stabilization of the base pair open state is due to a 'conformational switch' comprised of 2'OH(n)-O4'(n+1) hydrogen bonding and a rigid body motion of the nucleoside moiety in RNA. This rigid body motion is associated with decreased flexibility of the glycosyl linkage and sugar moieties in A-form structures. The observed opening rates in RNA are consistent with the imino proton exchange experiments for AU base pairs, although not for GC base pairs, while structural and flexibility changes associated with the proposed conformational switch are consistent with survey data of RNA and DNA crystal structures. The possible relevance of base pair opening events in RNA to its many biological functions is discussed.

Base Pairing↗
PubMed2004

The relative flexibility of B-DNA and A-RNA duplexes: database analysis.

An extensive analysis of structural databases is carried out to investigate the relative flexibility of B-DNA and A-RNA duplexes in crystal form. Our results show that the general anisotropic concept of flexibility is not very useful to compare the deformability of B-DNA and A-RNA duplexes, since the flexibility patterns of B-DNA and A-RNA are quite different. In other words, 'flexibility' is a dangerous word for describing macromolecules, unless it is clearly defined. A few soft essential movements explain most of the natural flexibility of A-RNA, whereas many are necessary for B-DNA. Essential movements occurring in naked B-DNAs are identical to those necessary to deform DNA in DNA-protein complexes, which suggest that evolution has designed DNA-protein complexes so that B-DNA is deformed according to its natural tendency. DNA is generally more flexible, but for some distortions A-RNA is easier to deform. Local stiffness constants obtained for naked B-DNAs and DNA complexes are very close, demonstrating that global distortions in DNA necessary for binding to proteins are the result of the addition of small concerted deformations at the base-pair level. Finally, it is worth noting that in general the picture of the relative deformability of A-RNA and DNA derived from database analysis agrees very well with that derived from state of the art molecular dynamics (MD) simulations.

Crystallography, X-Ray↗
PubMed2005

New insights into DNA triplexes: residual twist and radial difference as measures of base triplet non-isomorphism and their implication to sequence-dependent non-uniform DNA triplex.

DNA triplexes are formed by both isomorphic (structurally alike) and non-isomorphic (structurally dissimilar) base triplets. It is espoused here that (i) the base triplet non-isomorphism may be articulated in structural terms by a residual twist (Delta(t) degrees), the angle formed by line joining the C1'...C1' atoms of the adjacent Hoogsteen or reverse Hoogsteen (RH) base pairs and the difference in base triplet radius (Delta(r) A), and (ii) their influence on DNA triplex is largely mechanistic, leading to the prediction of a high (t + Delta(t))degrees and low (t - Deltat)degrees twist at the successive steps of Hoogsteen or RH duplex of a parallel or antiparallel triplex. Efficacy of this concept is corroborated by molecular dynamics (MD) simulation of an antiparallel DNA triplex comprising alternating non-isomorphic G*GC and T*AT triplets. Conformational changes necessitated by base triplet non-isomorphism are found to induce an alternating (i) high anti and anti glycosyl and (ii) BII and an unusual BIII conformation resulting in a zigzag backbone for the RH strand. Thus, base triplet non-isomorphism causes DNA triplexes into exhibiting sequence-dependent non-uniform conformation. Such structural variations may be relevant in deciphering the specificity of interaction with DNA triplex binding proteins. Seemingly then, residual twist (Delta(t) degrees) and radial difference (Deltar A) suffice as indices to define and monitor the effect of base triplet non-isomorphism in nucleic acid triplexes.

Base Pairing↗
PubMed2006

Structural and evolutionary classification of G/U wobble basepairs in the ribosome.

We present a comprehensive structural, evolutionary and molecular dynamics (MD) study of the G/U wobble basepairs in the ribosome based on high-resolution crystal structures, including the recent Escherichia coli structure. These basepairs are classified according to their tertiary interactions, and sequence conservation at their positions is determined. G/U basepairs participating in tertiary interactions are more conserved than those lacking any interactions. Specific interactions occurring in the G/U shallow groove pocket--like packing interactions (P-interactions) and some phosphate backbone interactions (phosphate-in-pocket interactions)--lead to higher G/U conservation than others. Two salient cases of unique phylogenetic compensation are discovered. First, a P-interaction is conserved through a series of compensatory mutations involving all four participating nucleotides to preserve or restore the G/U in the optimal orientation. Second, a G/U basepair forming a P-interaction and another one forming a phosphate-in-pocket interaction are replaced by GNRA loops that maintain similar tertiary contacts. MD simulations were carried out on eight P-interactions. The specific GU/CG signature of this interaction observed in structure and sequence analysis was rationalized, and can now be used for improving sequence alignments.

Base Pairing↗