165 research outputs found
Major G-Quadruplex Form of HIV-1 LTR Reveals a (3 + 1) Folding Topology Containing a Stem-Loop
Nucleic acids can form noncanonical four-stranded structures called G-quadruplexes. G-quadruplex-forming sequences are found in several genomes including human and viruses. Previous studies showed that the G-rich sequence located in the U3 promoter region of the HIV-1 long terminal repeat (LTR) folds into a set of dynamically interchangeable G-quadruplex structures. G-quadruplexes formed in the LTR could act as silencer elements to regulate viral transcription. Stabilization of LTR G-quadruplexes by G-quadruplex-specific ligands resulted in decreased viral production, suggesting the possibility of targeting viral G-quadruplex structures for antiviral purposes. Among all the G-quadruplexes formed in the LTR sequence, LTR-III was shown to be the major G-quadruplex conformation in vitro. Here we report the NMR structure of LTR-III in K+ solution, revealing the formation of a unique quadruplex-duplex hybrid consisting of a three-layer (3 + 1) G-quadruplex scaffold, a 12-nt diagonal loop containing a conserved duplex-stem, a 3-nt lateral loop, a 1-nt propeller loop, and a V-shaped loop. Our structure showed several distinct features including a quadruplex-duplex junction, representing an attractive motif for drug targeting. The structure solved in this study may be used as a promising target to selectively impair the viral cycle
Phase Behavior of Columnar DNA Assemblies
The pair interaction between two stiff parallel linear DNA molecules depends
not only on the distance between their axes but on their azimuthal orientation.
The positional and orientational order in columnar B-DNA assemblies in solution
is investigated, based on the DNA-DNA electrostatic pair potential that takes
into account DNA helical symmetry and the amount and distribution of adsorbed
counterions. A phase diagram obtained by lattice sum calculations predicts a
variety of positionally and azimuthally ordered phases and bundling transitions
strongly depending on the counterion adsorption patterns.Comment: 4 pages, 3 figures, submitted to PR
Stick-release pattern in stretching single condensed polyelectrolyte toroids
Using Langevin dynamics simulations, we study elastic response of single
semiflexible polyelectrolytes to an external force pulling on the chain ends,
to mimic the stretching of DNA molecules by optical tweezers. The linear chains
are condensed by multivalent counterions into toroids. The force-extension
curve shows a series of sawtooth-like structure, known as the stick-release
patterns in experiments. We demonstrate that these patterns are a consequence
of the loop-by-loop unfolding of the toroidal structure. Moreover, the
dynamics, how the internal structure of chain varies under tension, is
examined. At the first stage of the stretching, the toroidal condensate
decreases its size until the loss of the first loop in the toroid and then,
oscillates around this size for the rest of the unfolding process. The normal
vector of the toroid is pulled toward the pulling-force direction and swings
back to its early direction repeatedly when the toroidal chain looses a loop.
The results provide new and valuable information concerning the elasticity and
the microscopic structure and dynamic pathway of salt-condensed DNA molecules
being stretched.Comment: 13 pages, 5 figures, accepted for publication in Macromolecule
Effective interaction between helical bio-molecules
The effective interaction between two parallel strands of helical
bio-molecules, such as deoxyribose nucleic acids (DNA), is calculated using
computer simulations of the "primitive" model of electrolytes. In particular we
study a simple model for B-DNA incorporating explicitly its charge pattern as a
double-helix structure. The effective force and the effective torque exerted
onto the molecules depend on the central distance and on the relative
orientation. The contributions of nonlinear screening by monovalent counterions
to these forces and torques are analyzed and calculated for different salt
concentrations. As a result, we find that the sign of the force depends
sensitively on the relative orientation. For intermolecular distances smaller
than it can be both attractive and repulsive. Furthermore we report a
nonmonotonic behaviour of the effective force for increasing salt
concentration. Both features cannot be described within linear screening
theories. For large distances, on the other hand, the results agree with linear
screening theories provided the charge of the bio-molecules is suitably
renormalized.Comment: 18 pages, 18 figures included in text, 100 bibliog
Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence
Human telomeric DNA consists of tandem repeats of the DNA sequence d(GGGTTA). Oligodeoxynucletotide telomere models such as d[A(GGGTTA)(3)GGG] (Tel22) fold in a cation-dependent manner into quadruplex structures consisting of stacked G-quartets linked by d(TTA) loops. NMR has shown that in Na(+) solutions Tel22 forms a ‘basket’ topology of four antiparallel strands; in contrast, Tel22 in K(+) solutions consists of a mixture of unknown topologies. Our previous studies on the mechanism of folding of Tel22 and similar telomere analogs utilized changes in UV absorption between 270 and 325 nm that report primarily on G-quartet formation and stacking showed that quadruplex formation occurs within milliseconds upon mixing with an appropriate cation. In the current study, we assessed the dynamics and equilibria of folding of specific loops by using Tel22 derivatives in which the dA residues were serially substituted with the fluorescent reporter base, 2-aminopurine (2-AP). Tel22 folding induced by Na(+) or K(+) assessed by changes in 2-AP fluorescence consists of at least three kinetic steps with time constants spanning a range of ms to several hundred seconds. Na(+)-dependent equilibrium titrations of Tel22 folding could be approximated as a cooperative two-state process. In contrast, K(+)-dependent folding curves were biphasic, revealing that different conformational ensembles are present in 1 mM and 30 mM K(+). This conclusion was confirmed by (1)H NMR. Molecular dynamics simulations revealed a K(+) binding pocket in Tel22 located near dA1 that is specific for the so-called hybrid-1 conformation in which strand 1 is in a parallel arrangement. The possible presence of this topologically specific binding site suggests that K(+) may play an allosteric role in regulating telomere conformation and function by modulating quadruplex tertiary structure
Universal Sequence Replication, Reversible Polymerization and Early Functional Biopolymers: A Model for the Initiation of Prebiotic Sequence Evolution
Many models for the origin of life have focused on understanding how evolution can drive the refinement of a preexisting enzyme, such as the evolution of efficient replicase activity. Here we present a model for what was, arguably, an even earlier stage of chemical evolution, when polymer sequence diversity was generated and sustained before, and during, the onset of functional selection. The model includes regular environmental cycles (e.g. hydration-dehydration cycles) that drive polymers between times of replication and functional activity, which coincide with times of different monomer and polymer diffusivity. Template-directed replication of informational polymers, which takes place during the dehydration stage of each cycle, is considered to be sequence-independent. New sequences are generated by spontaneous polymer formation, and all sequences compete for a finite monomer resource that is recycled via reversible polymerization. Kinetic Monte Carlo simulations demonstrate that this proposed prebiotic scenario provides a robust mechanism for the exploration of sequence space. Introduction of a polymer sequence with monomer synthetase activity illustrates that functional sequences can become established in a preexisting pool of otherwise non-functional sequences. Functional selection does not dominate system dynamics and sequence diversity remains high, permitting the emergence and spread of more than one functional sequence. It is also observed that polymers spontaneously form clusters in simulations where polymers diffuse more slowly than monomers, a feature that is reminiscent of a previous proposal that the earliest stages of life could have been defined by the collective evolution of a system-wide cooperation of polymer aggregates. Overall, the results presented demonstrate the merits of considering plausible prebiotic polymer chemistries and environments that would have allowed for the rapid turnover of monomer resources and for regularly varying monomer/polymer diffusivities
Bimolecular quadruplexes and their transitions to higher-order molecular structures detected by ESI-FTICR-MS
Regularity Properties and Pathologies of Position-Space Renormalization-Group Transformations
We reconsider the conceptual foundations of the renormalization-group (RG)
formalism, and prove some rigorous theorems on the regularity properties and
possible pathologies of the RG map. Regarding regularity, we show that the RG
map, defined on a suitable space of interactions (= formal Hamiltonians), is
always single-valued and Lipschitz continuous on its domain of definition. This
rules out a recently proposed scenario for the RG description of first-order
phase transitions. On the pathological side, we make rigorous some arguments of
Griffiths, Pearce and Israel, and prove in several cases that the renormalized
measure is not a Gibbs measure for any reasonable interaction. This means that
the RG map is ill-defined, and that the conventional RG description of
first-order phase transitions is not universally valid. For decimation or
Kadanoff transformations applied to the Ising model in dimension ,
these pathologies occur in a full neighborhood of the low-temperature part of the first-order
phase-transition surface. For block-averaging transformations applied to the
Ising model in dimension , the pathologies occur at low temperatures
for arbitrary magnetic-field strength. Pathologies may also occur in the
critical region for Ising models in dimension . We discuss in detail
the distinction between Gibbsian and non-Gibbsian measures, and give a rather
complete catalogue of the known examples. Finally, we discuss the heuristic and
numerical evidence on RG pathologies in the light of our rigorous theorems.Comment: 273 pages including 14 figures, Postscript, See also
ftp.scri.fsu.edu:hep-lat/papers/9210/9210032.ps.
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