arXiv subjects

Alexey K. Mazur

Publications and source records attributed to Alexey K. Mazur.

At least 19 recordsLinked to original sources

arXiv2022

Direct pairing of homologous DNA double helices may involve the B-to-C form transition

In many organisms, homologous (or repetitive) chromosomal regions can associate or/and undergo concerted epigenetic changes in the absence of DNA breakage and recombination. The direct specific pairing of DNA duplexes with similar nucleotide sequences represents an attractive mechanism for recognizing such regions. Whereas the pairing of B-DNA duplexes may involve a large energy barrier, C-DNA duplexes are expected to pair much more readily. This unique feature of C-DNA is largely due to the fact that its major groove is wide and very shallow, permitting almost perfect initial homologous contacts between two duplexes without clashing. Overall, the conjectured role of C-DNA in recombination-independent pairing should revive the efforts to understand its structure and function in the cell.

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arXiv2019

Direct homologous dsDNA-dsDNA pairing: how, where and why?

The ability of homologous chromosomes (or selected chromosomal loci) to pair specifically in the apparent absence of DNA breakage and recombination represents a prominent feature of eukaryotic biology. The mechanism of homology recognition at the basis of such recombination-independent pairing has remained elusive. A number of studies have supported the idea that sequence homology can be sensed between intact DNA double helices in vivo. In particular, recent analyses of the two silencing phenomena in fungi, known as repeat-induced point mutation (RIP) and meiotic silencing by unpaired DNA (MSUD), have provided genetic evidence for the existence of the direct homologous dsDNA-dsDNA pairing. Both RIP and MSUD likely rely on the same search strategy, by which dsDNA segments are matched as arrays of interspersed base-pair triplets. This process is general and very efficient, yet it proceeds normally without the RecA/Rad51/Dmc1 proteins. Further studies of RIP and MSUD may yield surprising insights into the function of DNA in the cell.

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arXiv2017

Weak Nanoscale Chaos And Anomalous Relaxation in DNA

Anomalous non-exponential relaxation in hydrated biomolecules is commonly attributed to the complexity of the free-energy landscapes, similarly to polymers and glasses. It was found recently that the hydrogen-bond breathing of terminal DNA base pairs exhibits a slow power-law relaxation attributable to weak Hamiltonian chaos, with parameters similar to experimental data. Here, the relationship is studied between this motion and spectroscopic signals measured in DNA with a small molecular photoprobe inserted into the base-pair stack. To this end, the earlier computational approach in combination with an analytical theory is applied to the experimental DNA fragment. It is found that the intensity of breathing dynamics is strongly increased in the internal base pairs that flank the photoprobe, with anomalous relaxation quantitatively close to that in terminal base pairs. A physical mechanism is proposed to explain the coupling between the relaxation of base-pair breathing and the experimental response signal. It is concluded that the algebraic relaxation observed experimentally is very likely a manifestation of weakly chaotic dynamics of hydrogen-bond breathing in the base pairs stacked to the photoprobe, and that the weak nanoscale chaos can represent an ubiquitous hidden source of non-exponential relaxation in ultrafast spectroscopy.

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arXiv2016

Homologous Pairing between Long DNA Double Helices

Molecular recognition between two double stranded (ds) DNA with homologous sequences may not seem compatible with the B-DNA structure because the sequence information is hidden when it is used for joining the two strands. Nevertheless, it has to be invoked to account for various biological data. Using quantum chemistry, molecular mechanics, and hints from recent genetics experiments I show here that direct recognition between homologous dsDNA is possible through formation of short quadruplexes due to direct complementary hydrogen bonding of major groove surfaces in parallel alignment. The constraints imposed by the predicted structures of the recognition units determine the mechanism of complexation between long dsDNA. This mechanism and concomitant predictions agree with available experimental data and shed light upon the sequence effects and the possible involvement of topoisomerase II in the recognition.

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arXiv2015

Algebraic statistics of Poincaré recurrences in DNA molecule

Statistics of Poincaré recurrences is studied for the base-pair breathing dynamics of an all-atom DNA molecule in realistic aqueous environment with thousands of degrees of freedom. It is found that at least over five decades in time the decay of recurrences is described by an algebraic law with the Poincaré exponent close to $β=1.2$. This value is directly related to the correlation decay exponent $ν= β-1$, which is close to $ν\approx 0.15$ observed in the time resolved Stokes shift experiments. By applying the virial theorem we analyse the chaotic dynamics in polynomial potentials and demonstrate analytically that exponent $β=1.2$ is obtained assuming the dominance of dipole-dipole interactions in the relevant DNA dynamics. Molecular dynamics simulations also reveal the presence of strong low frequency noise with the exponent $η=1.6$. We trace parallels with the chaotic dynamics of symplectic maps with a few degrees of freedom characterized by the Poincaré exponent $β\sim 1.5$.

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arXiv2014

DNA flexibility on short length scales probed by atomic force microscopy

Unusually high bending flexibility has been recently reported for DNA on short length scales. We use atomic force microscopy (AFM) in solution to obtain a direct estimate of DNA bending statistics for scales down to one helical turn. It appears that DNA behaves as a Gaussian chain and is well described by the worm-like chain model at length scales beyond 3 helical turns (10.5nm). Below this threshold, the AFM data exhibit growing noise because of experimental limitations. This noise may hide small deviations from the Gaussian behavior, but they can hardly be significant.

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arXiv2013

Comments on "Length scale dependence of DNA mechanical properties"

Recent experimental data indicate that the elastic wormlike rod model of DNA that works well on long length scales may break down on shorter scales relevant to biology. According to Noy and Golestanian (Phys. Rev. Lett. 109, 228101, 2012) molecular dynamics (MD) simulations predict DNA rigidity close to experimental data and confirm one scenario of such breakdown, namely, that for lengths of a few helical turns, DNA dynamics exhibit long-range bending and stretching correlations. Earlier studies using similar forcefields concluded that (i) MD systematically overestimate the DNA rigidity, and (ii) no deviations from the WLR model are detectable. Here it is argued that the data analysis in the above mentioned paper was incorrect and that the earlier conclusions are valid.

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arXiv2012

The torque transfer coefficient in DNA under torsional stress

In recent years, significant progress in understanding the properties of supercoiled DNA has been obtained due to nanotechniques that made stretching and twisting of single molecules possible. Quantitative interpretation of such experiments requires accurate knowledge of torques inside manipulated DNA. This paper argues that it is not possible to transfer the entire magnitudes of external torques to the twisting stress of the double helix, and that a reducing torque transfer coefficient (TTC<1) should always be assumed. This assertion agrees with simple physical intuition and is supported by the results of all-atom molecular dynamics (MD) simulations. According to MD, the TTCs around 0.8 are observed in nearly optimal conditions. Reaching higher values requires special efforts and it should be difficult in practice. The TTC can be partially responsible for the persistent discrepancies between the twisting rigidity of DNA measured by different methods.

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arXiv2011

Local elasticity of strained DNA studied by all-atom simulations

Genomic DNA is constantly subjected to various mechanical stresses arising from its biological functions and cell packaging. If the local mechanical properties of DNA change under torsional and tensional stress, the activity of DNA-modifying proteins and transcription factors can be affected and regulated allosterically. To check this possibility, appropriate steady forces and torques were applied in the course of all-atom molecular dynamics simulations of DNA with AT- and GC-alternating sequences. It is found that the stretching rigidity grows with tension as well as twisting. The torsional rigidity is not affected by stretching, but it varies with twisting very strongly, and differently for the two sequences. Surprisingly, for AT-alternating DNA it passes through a minimum with the average twist close to the experimental value in solution. For this fragment, but not for the GC-alternating sequence, the bending rigidity noticeably changes with both twisting and stretching. The results have important biological implications and shed light upon earlier experimental observations.

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arXiv2010

Anharmonic Torsional Stiffness of DNA Revealed under Small External Torques

DNA supercoiling plays an important role in a variety of cellular processes. The torsional stress related with supercoiling may be also involved in gene regulation through the local structure and dynamics of the double helix. To check this possibility steady torsional stress was applied to DNA in the course of all-atom molecular dynamics simulations. It is found that small static untwisting significantly reduces the torsional persistence length ($l_t$) of GC-alternating DNA. For the AT-alternating sequence a smaller effect of the opposite sign is observed. As a result, the measured $l_t$ values are similar under zero stress, but diverge with untwisting. The effect is traced to sequence-specific asymmetry of local torsional fluctuations, and it should be small in long random DNA due to compensation. In contrast, the stiffness of special short sequences can vary significantly, which gives a simple possibility of gene regulation via probabilities of strong fluctuations. These results have important implications for the role of local DNA twisting in complexes with transcription factors.

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arXiv2009

Analysis of Accordion DNA Stretching Revealed by The Gold Cluster Ruler

A promising new method for measuring intramolecular distances in solution uses small-angle X-ray scattering interference between gold nanocrystal labels (Mathew-Fenn et al, Science, 322, 446 (2008)). When applied to double stranded DNA, it revealed that the DNA length fluctuations are strikingly strong and correlated over at least 80 base pair steps. In other words, the DNA behaves as accordion bellows, with distant fragments stretching and shrinking concertedly. This hypothesis, however, disagrees with earlier experimental and computational observations. This Letter shows that the discrepancy can be rationalized by taking into account the cluster exclusion volume and assuming a moderate long-range repulsion between them. The long-range interaction can originate from an ion exclusion effect and cluster polarization in close proximity to the DNA surface.

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arXiv2009

Comments on "Remeasuring the Double Helix"

Mathew-Fenn et al. (Science (2008) 322, 446-9) measured end-to-end distances of short DNA and concluded that stretching fluctuations in several consecutive turns of the double helix should be strongly correlated. I argue that this conclusion is based on incorrect assumptions, notably, on a simplistic treatment of the excluded volume effect of reporter labels. Contrary to the author's claim, their conclusion is not supported by other data.

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arXiv2007

The Worm-Like Chain Theory And Bending Of Short DNA

The probability distributions for bending angles in double helical DNA obtained in all-atom molecular dynamics simulations are compared with theoretical predictions. The computed distributions remarkably agree with the worm-like chain theory for double helices of one helical turn and longer, and qualitatively differ from predictions of the semi-elastic chain model. The computed data exhibit only small anomalies in the apparent flexibility of short DNA and cannot account for the recently reported AFM data (Wiggins et al, Nature nanotechnology 1, 137 (2006)). It is possible that the current atomistic DNA models miss some essential mechanisms of DNA bending on intermediate length scales. Analysis of bent DNA structures reveals, however, that the bending motion is structurally heterogeneous and directionally anisotropic on the intermediate length scales where the experimental anomalies were detected. These effects are essential for interpretation of the experimental data and they also can be responsible for the apparent discrepancy.

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arXiv2004

Sequence-dependent B-A transitions in DNA in silico: Electrostatic condensation mechanism

Dynamics of the polymorphic A<->B transitions in DNA is compared for two polypurine sequences, poly(dA).poly(dT) and poly(dG).poly(dC), long known to exhibit contrasting properties in experiments. In free molecular dynamics simulations reversible transitions are induced by changing the size of a water drop around DNA neutralized by Na ions. In poly(dG).poly(dC) the B<->A transitions are easy, smooth and perfectly reversible. In contrast, a B->A transition in poly(dA).poly(dT) dodecamer fragment could not be obtained even though its A-form is stable under low hydration. Normal B->A transitions are observed, however, in long poly(dA).poly(dT) stretches flanked by GC pairs. An intermediate range of hydration numbers is identified where opposite transitions are observed in the two dodecamer fragments, namely, A->B in poly(dA).poly(dT) and B->A in poly(dG).poly(dC). With hydration numbers close to the stability limit of the B-form, the two sequences exhibit qualitatively different counterion distributions, with a characteristic accumulation of Na ions next to the opening of the minor groove in poly(dA).poly(dT). This difference can explain an increased persistence of poly(dA).poly(dT) DNA towards A-form in crystalline and amorphous fibers as compared to solution conditions. The good overall agreement with experimental data corroborates the general role of the electrostatic condensation mechanism in the A/B polymorphism in DNA.

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arXiv2003

Relaxation of DNA curvature by single stranded breaks: Simulations and experiments

The recently proposed compressed backbone theory suggested that the intrinsic curvature in DNA can result from a geometric mismatch between the specific backbone length and optimal base stacking orientations. It predicted that the curvature in A-tract repeats can be relaxed by introducing single stranded breaks (nicks). This effect has not been tested earlier and it would not be accounted for by alternative models of DNA bending. Here the curvature in a specifically designed series of nicked DNA fragments is tested experimentally by gel mobility assays and, simultaneously, by free molecular dynamics simulations. Single stranded breaks produce virtually no effect upon the gel mobility of the random sequence DNA. In contrast, nicked A-tract fragments reveal a regular modulation of curvature depending upon the position of the strand break with respect to the overall bend. Maximal relaxation is observed when nicks occur inside A-tracts. The results are partially reproduced in simulations. Analysis of computed curved DNA conformations reveals a group of sugar atoms that exhibit reduced backbone length within A-tracts, which can correspond to the compression hypothesis.

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arXiv2003

Reversible B/A Transitions in Single DNA Molecule Immersed in A Water Drop

Clarification of the detailed mechanisms involved in the DNA polymorphism is an important challenge for computational molecular biophysics. This paper reports about reversible A/B transitions in DNA observed in silico in a simulated titration experiment by smooth variation of the size of a water drop around a double helical solute. The estimated range of hydration numbers corresponding to the B/A transition roughly agrees with experimental data. The chain length dependence was studied and it appeared that the transition to A-form is hindered when the fragment becomes shorter than one helical turn. Dynamics of the A/B transition at low hydration is cooperative and is driven mainly by medium range electrostatic interactions of counterions sandwiched between phosphate strands in the major groove. The correspondence of these computational observations to common experimental conditions of A/B transitions is discussed.

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arXiv2002

DNA Dynamics in A Water Drop

Due to its polyionic character the DNA double helix is stable and biologically active only in salty aqueous media where its charge is compensated by solvent counterions. Monovalent metal ions are ubiquitous in DNA environment and they are usually considered as the possible driving force of sequence-dependent modulations of DNA structure that make it recognizable by proteins. In an effort to directly examine this hypothesis, MD simulations of DNA in a water drop surrounded by vacuum were carried out, which relieves the requirement of charge neutrality. Surprisingly, with zero concentration of counterions a dodecamer DNA duplex appears metastable and its structure remains similar to that observed in experiments.

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arXiv2001

Simulated and Experimental Bending Dynamics in DNA with and without A-Tracts

The macroscopic curvature of double helical DNA induced by regularly repeated adenine tracts is well-known but still puzzling. Its physical origin remains controversial even though it is perhaps the best-documented sequence modulation of DNA structure. We report here the results of comparative theoretical and experimental studies of bending dynamics in 35-mer DNA fragments. This length appears large enough for the curvature to be distinguished by gel electrophoresis. Two DNA fragments, with identical base pair composition, but different sequences are compared. In the first one, a single A-tract motif was four times repeated in phase with the helical screw whereas the second sequence was "random". Both calculations and experiments indicate that the A-tract DNA is distinguished by the large static curvature and characteristic bending dynamics, suggesting that the computed effect corresponds to the experimental phenomenon. The results poorly agree with earlier views that attributed a decisive role in DNA bending to sequence specific base pair stacking or binding of solvent counterions, but lend additional support to the hypothesis of a compressed frustrated state of the backbone as the principal physical cause of the static curvature. We discuss the possible ways of experimental verification of this hypothesis.

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