arXiv subjects

Davide Michieletto

Publications and source records attributed to Davide Michieletto.

At least 19 recordsLinked to original sources

arXiv2026

The Polymer Physics of Kinetoplast DNA as a Polymerised Membrane

We analyze the conformational and dynamical properties of the kinetoplast DNA (kDNA), a massive sheet-like structure made from thousands of circular DNA molecules, found in the mitochondrion of certain parasites. The connectivity between circular DNA molecules is achieved by topological linking, hence, the kDNA may be regarded as a naturally occurring two-dimensional version of Olympic gels, whose physical properties are yet to be understood. We propose that the basic aspects in the large scale behaviors of kDNA could be described by the physics of polymerized membrane. Our analysis indicates the relevance of the hydrodynamic interactions in the dynamics of kDNA in aqueous solution. We demonstrate that the predicted dynamical scaling scenario captures various experimental data recently obtained from {\it in vitro} imaging experiments in a unified manner. We also provide an estimate for the in-plane elastic modulus of kDNA, whose magnitude agrees well with recent measurements.

cond-mat.soft↗

arXiv2026

Writhe-Based Polymer Link Classification Using Machine Learning

Unique and rapid classification of knots and links is an open mathematical problem that is relevant to a range of (bio)physical systems, including polymer melts, DNA, and proteins. In this paper, we explore a data-driven approach to the classification problem of link topology. Extending the framework introduced in Ref. 1 (Sleiman et al, 2024 Soft Matter, 20(1), pp.71-78), we show that a feedforward neural network trained on the writhe density matrix classifies thermally equilibrated configurations of the first six prime links with 97% accuracy. We demonstrate that this accuracy remains high across a range of temperatures and lengths of link components, while rapidly deteriorating with the addition of topology-altering Gaussian noise; a result consistent with the writhe density matrix containing features sensitive to topology. Our results show that neural networks based on the writhe density matrix efficiently classify two-component links, establishing machine learning as a promising tool for rapid classification of more complex link topologies, e.g. Borromean rings and multi-component links, as the computational cost of exact numerical calculation of topological invariants becomes prohibitive.

math.GT↗

arXiv2026

Designing DNA nanostar hydrogels with programmable degradation and antibody release

DNA nanostar (DNAns) hydrogels are promising materials for \textit{in vivo} applications, including tissue regeneration and drug and antibody delivery. However, a systematic and quantitative understanding of the design principles controlling their degradation is lacking. Here, we investigate hydrogels made of three-armed DNAns with varying flexible joints, arm lengths, and mesh sizes and use restriction enzymes (RE) to cut the DNAns structures while monitoring the gel's degradation. We discover that (i) removing flexible joints, (ii) increasing arm length, or (iii) relocating the RE site along a DNA linker markedly accelerates hydrogel degradation. In contrast, non-specific endonucleases, e.g. DNaseI, quickly degrade DNAns hydrogels regardless of design. Importantly, the release of antibodies from DNAns hydrogels can be modulated by the action of sequence-specific enzymes, confirming that programmable degradation can be leveraged for responsive drug-delivery systems. These findings provide a better understanding of the design principles for DNAns-based scaffolds with tunable degradation, cargo release, and responsive rheology.

cond-mat.soft↗

arXiv2026

NANOG assembles into self-limiting aging micelles that drive a sol-gel transition and modulate DNA dynamics

Proteins and nucleic acids form non-Newtonian liquids with complex rheological properties that contribute to their function in vivo. Here we investigate the rheology of the transcription factor NANOG, a key protein to maintain embryonic stem cell pluripotency. We find that at high concentrations, NANOG forms macroscopic aging gels that are dependent on its intrinsically disordered domain. By combining molecular dynamics simulations, mass photometry and Cryo-EM, we also discover that -- in contrast with unbounded condensates formed by other intrinsically disordered proteins -- NANOG forms self-limiting micelles with exposed DNA-binding domains. We show that these micelles can stabilize DNA entanglements and in turn modulate DNA dynamics. Based on our findings, we conjecture that NANOG may contribute to regulate gene expression by creating local gel-like environments that restrict genome dynamics and that its aging may ingrain mechanical memory in gene regulatory networks.

cond-mat.soft↗

arXiv2026

Rheology and Programmable Gelation of DNA Origami Polymer Tadpoles

DNA origami is a powerful method to achieve nanoscale folded structures. Despite rapid improvements in folding and purification methods, DNA origami objects are still often produced in small quantities and studied at single molecule scale. Here, we design simple DNA origami-inspired polymers with complex topologies, and study their rheology and viscoelastic properties in dense conditions. First, we designed and purified topologically distinct DNA nanostructures, linear, circular, and "tadpole" polymers, to evaluate how polymer architecture influences entanglement and rheology. Despite their distinct topologies, we observe that all constructs obeyed universal rheological scalings, likely due to their short length. However, upon thermal annealing in the bulk, the DNA origami-like polymers displayed significantly different behaviours. Our results suggest that DNA origami-like polymers could be used to engineer thermoresponsive behaviours in complex fluids by introducing reversible and topology-dependent crosslinking.

cond-mat.soft↗

arXiv2026

Yeast condensin acts as a transient intermolecular crosslinker in entangled DNA

Structural-Maintenance-of-Chromosome (SMC) complexes such as condensins organise the folding of chromosomes. However, their role in modulating the entanglement of DNA and chromatin is not fully understood. To address this question, we perform single molecule and bulk characterisation of yeast condensin in entangled DNA. First, we discover that yeast condensin can proficiently bind double-stranded DNA through its hinge domain, in addition to its heads. Through bulk microrheology assays we then discover that physiological concentrations of yeast condensin increase both the viscosity and elasticity of dense solutions of lambda-DNA suggesting that condensin acts as a crosslinker in entangled DNA, stabilising entanglements rather than resolving them and contrasting the popular theoretical picture where SMCs purely drive the formation of segregated, bottle-brush-like chromosome structures. We further discover that the presence of ATP fluidifies the solution -- likely by activating loop extrusion -- but does not recover the viscosity measured in the absence of protein. Finally, we show that the observed rheology can be understood by modelling SMCs as transient crosslinkers in bottle-brush-like entangled polymers. Our findings help us to understand how SMCs affect the dynamics and entanglement of genomes.

cond-mat.soft↗

arXiv2026

The Integration Host Factor is a pH-responsive protein that switches from DNA bending to DNA bridging in acidic biofilm-like conditions

The Integration Host Factor (IHF) is a nucleoid-associated protein critical for both DNA compaction and biofilm stability. While its role in DNA packaging within the cell is well understood, its structural role in scaffolding biofilms is more puzzling and difficult to reconcile with its known DNA bending activity. Here, we investigated how IHF-DNA interactions are modulated across a pH spectrum mimicking the acidic microenvironments of bacterial biofilms. By performing all-atom calculations we discovered that low pHs lead to a change in protonation of IHF residues, which in turn exposes positively charged patches. We then conjectured that these positively charged residues could lead to intermolecular DNA bridging and tested this hypothesis through single-molecule and bulk assays. We discovered that while at physiological pH IHF mostly bends DNA, at pH < 5 there is clear evidence of IHF-mediated intermolecular crosslinking. Our results demonstrate that pH significantly modulates IHF-DNA interactions and explains the structural role played by IHF in supporting biofilm mechanics through intermolecular crosslinking.

cond-mat.soft↗

arXiv2026

Shortcut learning in geometric knot classification

Classifying the topology of closed curves is a central problem in low dimensional topology with applications beyond mathematics spanning protein folding, polymer physics and even magnetohydrodynamics. The central problem is how to determine whether two embeddings of a closed arc are equivalent under ambient isotopy. Given the striking ability of neural networks to solve complex classification tasks, it is therefore natural to ask if the knot classification problem can be tackled using Machine Learning (ML). In this paper, we investigate generic shortcut methods employed by ML to solve the knot classification challenge and specifically discover hidden non-topological features in training data generated through Molecular Dynamics simulations of polygonal knots that are used by ML to arrive to positive classifications results. We then provide a rigorous foundation for future attempts to tackle the knot classification challenge using ML by developing a publicly-available (i) dataset, that aims to remove the potential of non-topological feature classification and (ii) code, that can generate knot embeddings that faithfully explore chosen geometric state space with fixed knot topology. We expect that our work will accelerate the development of ML models that can solve complex geometric knot classification challenges.

cs.LG↗

arXiv2025

Binding Kinetics Oppositely Regulates type II Topoisomerase Relaxation and Decatenation Activities

Type II Topoisomerases (topo II) are critical to simplify genome topology during transcription and replication. They identify topological problems and resolve them by passing a double-stranded DNA segment through a transient break in another segment. The precise mechanisms underpinning topo IIs ability to maintain a topologically simple genome are not fully understood. Here, we investigate how binding kinetics affects the resolution of two distinct forms of topological entanglement: decatenation and torsional relaxation. First, by single-molecule measurements, we quantify how monovalent cation concentration affects the dissociation rate of topo II from DNA. Second, we discover that increasing dissociation rates accelerate decatenation while slowing down relaxation catalytic activities. Finally, by using molecular dynamics simulations, we uncover that this opposite behaviour is due to a trade-off between search of target through facilitated diffusion and processivity of the enzyme in catenated versus supercoiled DNA. Thus, our findings reveal that a modulation of topo II binding kinetics can oppositely regulate its topological simplification activity, and in turn can have a significant impact in vivo.

physics.bio-ph↗

arXiv2025

Modulation of DNA rheology by a transcription factor that forms aging microgels

Proteins and nucleic acids form non-Newtonian liquids with complex rheological properties that contribute to their function in vivo. Here we investigate the rheology of the transcription factor NANOG, a key protein in sustaining embryonic stem cell self-renewal. We discover that at high concentrations NANOG forms macroscopic aging gels through its intrinsically disordered tryptophan-rich domain. By combining molecular dynamics simulations, mass photometry and Cryo-EM, we also discover that NANOG forms self-limiting micelle-like clusters which expose their DNA-binding domains. In dense solutions of DNA, NANOG micelle-like structures stabilize intermolecular entanglements and crosslinks, forming microgel-like structures. Our findings suggest that NANOG may contribute to regulate gene expression in a unconventional way: by restricting and stabilizing genome dynamics at key transcriptional sites through the formation of an aging microgel-like structure, potentially enabling mechanical memory in the gene network.

cond-mat.soft↗

arXiv2025

Organisation and dynamics of individual DNA segments in topologically complex genomes

Capturing the physical organisation and dynamics of genomic regions is one of the major open challenges in biology. The kinetoplast DNA (kDNA) is a topologically complex genome, made by thousands of DNA (mini and maxi) circles interlinked into a two-dimensional Olympic network. The organisation and dynamics of these DNA circles are poorly understood. In this paper, we show that dCas9 linked to Quantum Dots can efficiently label different classes of DNA minicircles in kDNA. We use this method to study the distribution and dynamics of different classes of DNA minicircles within the network. We discover that maxicircles display a preference to localise at the periphery of the network and that they undergo subdiffusive dynamics. From the latter, we can also quantify the effective network stiffness, confirming previous indirect estimations via AFM. Our method could be used more generally, to quantify the location, dynamics and material properties of genomic regions in other complex genomes, such as that of bacteria, and to study their behaviour in the presence of DNA-binding proteins.

cond-mat.soft↗

arXiv2025

Topological Linking Determines Elasticity in Limited Valence Networks

Understanding the relationship between the microscopic structure and topology of a material and its macroscopic properties is a fundamental challenge across a wide range of systems. Here, we investigate the viscoelasticity of DNA nanostar hydrogels - a model system for physical networks with limited valence - by coupling rheology measurements, confocal imaging and molecular dynamics simulations. We discover that these networks display a large degree of interpenetration and that loops within the network are topologically linked, forming a percolating network-within-network structure. Below overlapping concentration, the fraction of branching points and the pore size determine the high-frequency elasticity of these physical gels. At higher concentrations, we discover that this elastic response is dictated by the abundance of topological links between looped motifs in the gel. Our findings highlight the emergence of "topological elasticity" as a previously overlooked mechanism in generic network-forming liquids and gels and inform the design of topologically-controllable material behaviours.

cond-mat.soft↗

arXiv2024

Persistent Homology Reveals the Role of Stiffness in Forming Topological Glasses in Dense Solutions of Ring Polymers

Ring polymers are characterized by topology-specific entanglements called threadings. In the limit of large rings, it is conjectured that a "topological glass" should emerge due to the proliferation of threadings. In this study, we used persistent homology to quantify threading structures of ring polymers with different chain stiffness and elucidate mechanisms behind topological glasses. Using coordination data from coarse-grained molecular dynamics simulations, we analyzed the topology of the union of virtual spheres centered on each monomer or center of mass. As the radius of each sphere increases, the corresponding points connect, giving rise to topological entities such as edges, loops, and facets. We then analyzed how the number of loops per ring chain and penetrated loops varies with sphere radius, focusing on the effects of chain stiffness and density. The results reveal that loops are larger in stiff ring chains, whereas flexible ring chains do not generate sufficiently large loops to establish a threading structure. The stiffness of ring polymer plays a significant role in the formation of topological glasses in ring polymers.

cond-mat.soft↗

arXiv2024

Fluidification of Entangled Polymers by Loop Extrusion

Loop extrusion is one of the main processes shaping chromosome organisation across the cell cycle, yet its role in regulating DNA entanglement and nucleoplasm viscoelasticity remains overlooked. We simulate entangled solutions of linear polymers under the action of generic Loop Extruding Factors (LEF) with a model that fully accounts for topological constraints and LEF-DNA uncrossability. We discover that extrusion drives the formation of bottle-brush-like structures which significantly lower the entanglement and effective viscosity of the system through an active fluidification mechanism. Interestingly, this fluidification displays an optimum at one LEF every 300-3000 basepairs. In marked contrast with entangled linear chains, the viscosity of extruded chains scales linearly with polymer length, yielding up to 1000-fold fluidification. Our results illuminate how loop extrusion contributes to actively modulate genome entanglement and viscoelasticity in vivo.

cond-mat.soft↗

arXiv2024

Kinetoplast DNA: a polymer physicist's Olympic dream

All life forms are miraculous, but some are more inexplicable than others. Trypanosomes are by far one of the most puzzling organisms on Earth: their mitochondrial genome, also called kinetoplast DNA (kDNA) forms an Olympic-ring-like network of interlinked DNA circles, challenging conventional paradigms in both biology and physics. In this review, I will discuss kDNA from the astonished perspective of a polymer physicist and tell a story of how a single sub-celluar structure from a blood-dwelling parasite is inspiring generations of polymer chemists and physicists to create new catenated materials.

cond-mat.soft↗

arXiv2024

Link to Densify: Topological Transitions and Origin of Hysteresis During the (De)Compression of Amorphous Ices

In this Letter we study the phase transition between amorphous ices and the nature of the hysteresis cycle separating them. We discover that a topological transition takes place as the system transforms from low-density amorphous ice (LDA) at low pressures, to high-density amorphous ice (HDA) at high pressures. Specifically, we uncover that the hydrogen bond network (HBN) displays qualitatively different topologies in the LDA and HDA phases: the former characterised by disentangled loop motifs, while the latter displaying topologically complex and metastable Hopf-linked and knotted configurations. At the phase transition, the transient opening of the HBN topological motifs yields mechanical fragility on the macroscale. Our results provide a detailed microscopic description of the topological nature of the phase transition and the hysteresis cycle between amorphous ices. We argue that the topological transition discovered in this work may not only improve our understanding of amorphous ices but represent a generic mechanism for the densification of network-forming materials.

cond-mat.dis-nn↗

arXiv2024

Runaway Transition in Irreversible Polymer Condensation with Cyclisation

The process of polymer condensation, i.e. the formation of bonds between reactive end-groups, is ubiquitous in both industry and biology. Here we study generic systems undergoing polymer condensation in competition with cyclisation. Using a generalised Smoluchowski theory, molecular dynamics simulations and experiments using DNA and T4 ligase, we find that this system displays a transition, from a regime with finite-length chains at infinite time and dominated by rings to one dominated by linear polymers that grow in time. Finally, we show that fluids prepared close to the transition may have profoundly different compositions and rheology at large condensation times.

cond-mat.soft↗

arXiv2024

Effects of Monovalent and Divalent Cations on the Rheology of Entangled DNA

In this paper we investigate the effects of varying cation valency and concentration on the rheology of entangled lambda DNA solutions. We show that monovalent cations moderately increase the viscoelasticty of the solutions mainly by stabilising linear condensation of lambda DNA ``monomers'' via hybridisation of their sticky ends. On the contrary, divalent cations have a far more complex and dramatic effect on the rheology of the solution and we observe evidence of inter-molecular DNA-DNA bridging by Mg2+. We argue that these results may be interesting in the context of dense solutions of single and double stranded DNA, e.g. in vivo or in biotechnology applications such as DNA origami and DNA hydrogels.

cond-mat.soft↗