Biology subjects

Erbas, A.

Publications and source records attributed to Erbas, A..

12 recordsLinked to original sources

bioRxiv2026

Nonspecific steric hindrance of protein particles by lamina-associated domains

Genomic organization within the nucleus is crucial for gene regulation and cell health, as disruptions in this organization are linked to genetic disorders and cancers. Recent studies suggest that molecular-scale organization of chromatin near the nuclear periphery (lamina-associated domains, LADs) affects gene regulation, providing transciptional supression, but the biophysical mechanisms of supression behind remain unclear. LADs are large heterochromatic regions near the nuclear lamina, where transcriptional factors and RNA polymerase are scarce, implying a nonspecific filtering property. Here, we investigate the steric filtering capabilities of LADs by performing coarse-grained polymer simulations. Our results show that LAD thickness can be affected by the interaction between chromatin and nuclear periphery as well as chromatin self-compaction. Regardless, the LAD layer acts as a size-selective steric partitioning environment for protein particles limiting their access to nuclear periphery. Notably, increasing bulk protein levels enhances protein access linearly. These results align with experimental observations and suggest that LADs could control the presence of transcription machinery on the periphery of the nucleus, providing a polymer-physical mechanism for gene regulation in nuclei.

biophysics↗

bioRxiv2026

Inter-lamin interactions control meshwork topologyin a polymer-gel model of nuclear lamina

The nuclear lamina is a specialized two-dimensional filamentous polymer meshwork that provides structural integrity and elasticity to the nucleus while orchestrating diverse cellular processes. Composed of interacting A- and B-type lamin networks, this structure undergoes tightly regulated self-assembly that is frequently perturbed by disease-causing mutations such as those observed in laminopathies or cardiomyopathies. However, because filament assembly, peripheral adsorption of lamins, and network branching occur concurrently in vivo, isolating the specific biophysical parameters that dictate emergent lamina topology has remained a major challenge. Here, we present a polymer-physics approach that explicitly resolves the spontaneous self-assembly of lamin networks under nuclear confinement. By modeling lamin dimers as semiflexible filaments with distinct interactive domains, we demonstrate that the formation of continuous, high-aspect-ratio fibers strictly requires a coordination cascade of parallel lateral alignment sites and longitudinal head-to-tail interactions between lamins. We show that the thermodynamic affinity between lamin-A and the peripheral boundary (i.e., the inner nuclear membrane and lamin B network) acts as a kinetic switch: weak surface adsorption drives network phase separation and large lamin-free gaps, whereas robust substrate binding stabilizes highly branched networks with uniform lamin distribution. Finally, uniaxial compression simulations reveal that mutations altering these molecular binding interfaces severely compromise macroscale nuclear load-bearing capacity and induce structural vulnerabilities. Collectively, our model establishes a predictive, multi-scale view that directly bridges nanoscale lamin interactions with mesoscale topological remodeling of lamina and macroscale nuclear mechanopathology.

biophysics↗

bioRxiv2025

Peripheral heterochromatin tethering is required for chromatin-based nuclear mechanical response

The cell nucleus is a mechanically responsive structure that governs how external forces affect chromosomes. Chromatin, particularly transcriptionally inactive heterochromatin, resists nuclear deformations through its mechanical response. However, chromatin also exhibits liquid-like properties, casting ambiguity on the physical mechanisms of chromatin-based nuclear elasticity. To determine how heterochromatin strengthens nuclear mechanical response, we performed polymer physics simulations of a nucleus model validated by micromechanical measurements and chromosome conformation capture data. The attachment of peripheral heterochromatin to the lamina is required to transmit forces directly to the chromatin and elicit its elastic response. Thus, increases in heterochromatin levels increase nuclear rigidity by increasing the linkages between chromatin and the lamina. Crosslinks within heterochromatin, such as HP1 proteins, can also stiffen nuclei, but only if chromatin is peripherally tethered. In contrast, heterochromatin affinity interactions that may drive liquid-liquid phase separation do not contribute to nuclear rigidity. When the nucleus is stretched, gel-like peripheral heterochromatin can bear stresses and deform, while the more fluid-like interior euchromatin is less perturbed. Thus, heterochromatins internal structure and stiffness may regulate nuclear mechanics via peripheral attachment to the lamina, while also enabling nuclear mechanosensing of external forces and external measurement of the nucleus internal architecture.

biophysics↗

bioRxiv2024

Exploring Nuclear Lamina Structure and Lamin Dissociation in Progeria through Polymer Modeling

One of the key structural proteins in the eukaryotic cell nucleus is lamin. Lamins can assemble into a two-dimensional protein meshwork at the nuclear periphery, referred to as the nuclear lamina, which provides rigidity and shape to the nucleus. Mutations in lamin proteins that affect the structure of the nuclear lamina underlie laminopathic diseases, including Hutchinson-Gilford Progeria Syndrome (HGPS). Experiments have shown that, compared to healthy cells, lamin supramolecular structures (e.g., protofilaments) assemble into a thicker lamina structure in HGPS, where lamins form highly stable nematic microdomains at the nuclear periphery, reminiscent of liquid crystals. This significantly alters the morphological and mechanical properties of the nucleus. In this study, we investigate the aggregation of lamin fibrous structures and their dissociation kinetics from the nuclear periphery by modeling them as coarse-grained, rod-like polymer chains confined in a rigid spherical shell. Our model recapitulates the formation of multidirectional nematic domains at the nuclear surface and the reduced lamin dissociation observed in HGPS nuclei by adjusting lamin concentration, lamin-lamin (specifically head-tail), and lamin-shell association strengths. While nematic phase formation requires relatively strong lamin-shell affinity under any non-vanishing inter-lamin attraction, the thickness of this layer is primarily controlled by head-tail association strength in the model. Furthermore, the dissociation kinetics of lamin chains from the chain aggregates at the periphery (lamina) exhibits a concentration-dependent dissociation (facilitated dissociation) pattern governed by weak lamin-lamin interactions, reminiscent of healthy nuclei. Overall, our calculations demonstrate how an interplay between molecular interactions altered by mutations and lamin concentration can lead to an abnormal nuclear lamina in laminopathic diseases.

biophysics↗

bioRxiv2024

A polymer physics view of peripheral chromatin: de Gennes' self-similar carpet

Using scaling arguments to model peripheral chromatin localized near the inner surface of the nuclear envelope (NE) as a flexible polymer chain, we discuss the structural properties of the peripheral chromatin composed of alternating lamin-associated domains (LADs) and inter-LADs. Modeling the attraction of LADs to NE by de Gennes self-similar carpet, which treats the chromatin layer as a polymer fractal, explains two major experimental observations: (i) The high density of chromatin close to the nuclear periphery decays to a constant density as the distance to the periphery increases. (ii) Due to the decreasing mesh size towards the nuclear periphery, the chromatin carpet inside NE excludes molecules (via non-specific interactions) above a threshold size that depends on the distance from the nuclear periphery.

biophysics↗

bioRxiv2023

Polymer modelling suggests correlations between chromatin phase separation and nuclear shape fluctuations.

Abnormalities in the shapes of mammalian cell nuclei are hallmarks of a variety of diseases, including progeria, muscular dystrophy, and various cancers. Experiments have shown that there is a causal relationship between chromatin organization and nuclear morphology. Decreases in heterochromatin levels, perturbations to heterochromatin organization, and increases in euchromatin levels all lead to misshapen nuclei, which exhibit deformations, such as nuclear blebs and nuclear ruptures. However, the polymer physical mechanisms of how chromatin governs nuclear shape and integrity are poorly understood. To investigate how heterochromatin and euchromatin, which are thought to microphase separate in vivo, govern nuclear morphology, we implemented a composite coarse-grained polymer and elastic shell model. By varying chromatin volume fraction (density), heterochromatin levels and structure, and heterochromatin-lamina interactions, we show how the spatial organization of chromatin polymer phases within the nucleus could perturb nuclear shape in some scenarios. Increasing the volume fraction of chromatin in the cell nucleus stabilizes the nuclear lamina against large fluctuations. However, surprisingly, we find that increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations in our simulations by a "wetting"-like interaction. In contrast, shape fluctuations are largely insensitive to the internal structure of the heterochromatin, such as the presence or absence of chromatin-chromatin crosslinks. Therefore, our simulations suggest that heterochromatin accumulation at the nuclear periphery could perturb nuclear morphology in a nucleus or nuclear region that is sufficiently soft, while stabilization of the nucleus via heterochromatin likely occurs through mechanisms other than chromatin microphase organization.

biophysics↗

bioRxiv2023

Multi-exponential DNA Residence Behaviors of Transcription Factors Under The Discrete Affinity Model

The transcription process is regulated by temporal interactions of transcription factors with DNA. In the last decade, computational and experimental studies revealed the residence times of transcription factors on DNA correlate with transcriptional output. Biochemical studies suggest that transcription factor bindings exhibit bi-exponential dynamics, often explained by the binary affinity model composed of nonspecific and specific protein-DNA interactions. Recently, transcription factor residence times were shown to display a power law in vivo implicating effective protein-DNA interactions controlling the dissociation kinetics are rather more complex than suggested. One contribution that can cause such continuous residence-time distributions could be higher-order protein-DNA complexes or protein coacervates. Here, by using molecular dynamics simulations of a coarse-grained polymer model for bacterial chromosomes interacting with homodimeric transcription factors at physiologically relevant concentrations, we demonstrate that residence time distributions of dimeric proteins follow a multi-exponential pattern even when a single interaction describes the affinity between DNA and protein. Our simulations reveal that this emergent behavior is due to the formation of DNA-protein clusters of various sizes at a wide range of protein concentrations and affinities. These findings add another layer to transcriptional regulation and, consequently, to gene expression by connecting transcription factor concentrations and affinities, DNA-protein clusters, and DNA residence times of transcription factors.

biophysics↗

bioRxiv2023

Cyclic-polymer grafted colloids in spherical confinement: insights for interphase chromosome organization

Interphase chromosome structures are known to remain segregated in the micron-sized eukaryotic cell nucleus and occupy a certain fraction of nuclear volume, often without mixing. Using extensive coarse-grained simulations, we model such chromosome structures as colloidal particles whose surfaces are grafted by cyclic polymers. This model system is known as Rosetta. The cyclic polymers, with varying polymerization degrees, mimic the functionality of structural protein complexes, while the rigid core models the chromocenter sections of chromosomes. Our simulations show that the colloidal chromosome model provides a well-segregated particle distribution without specific attraction between the chain monomers. Notably, linear-polymer grafted particles also provide the same segregation scheme. However, unlike linear chains, cyclic chains result in less contact between the polymer layers of neighboring chromosome particles, demonstrating the effect of DNA breaks in altering genome-wide contacts. As the polymerization degree of the chains decreases while maintaining the total chromosomal length (the total polymer length per particle), particles form quasi-crystalline order, reminiscent of a glassy state. This order weakens for polymer chains with a characteristic size on the order of the confinement radius. Our simulations demonstrate that polymer systems can help decipher 3D chromosomal architectures along with fractal globular and loop-extrusion models.

biophysics↗

bioRxiv2021

Facilitated Dissociation of Nucleoid Associated Proteins from DNA in the Bacterial Confinement

Transcription machinery depends on the temporal formation of protein-DNA complexes. Recent experiments demonstrated that lifetime of the complex can also affect transcription. In parallel, in vitro single-molecule studies showed that nucleoid-associated proteins (NAPs) leave the DNA rapidly as the bulk concentration of the protein increases via facilitated dissociation (FD). Never-theless, whether such concentration-dependent mechanism is functional in a bacterial cell, in which NAP levels and the 3D chromosomal structure are often coupled, is not clear a priori. Here, by using extensive coarse-grained molecular simulations, we model the unbinding of specific and nonspecific dimeric NAPs from a high-molecular-weight circular DNA molecule in a cylindrical structure mimicking the cellular confinement of a bacterial chromosome. Our simulations show that physiologically relevant peak protein levels (tens of micromolar) lead to highly compact chromosomal structures. This compaction results in rapid off rates (shorter DNA-residence times) but only for specifically DNA-binding NAPs such as the factor for inversion stimulation (Fis). Contrarily, for nonspecific NAPs, the off rates decrease as the protein levels increase, suggesting an inverse FD pattern. The simulations with restrained chromosome models reveal that this inverse response is due to DNA-segmental fluctuations, and that chromosomal compaction is in favor of faster protein dissociation. Overall, our results indicate that cellular-concentration level of a structural DNA-binding protein can be highly intermingled with its DNA-residence time.

biophysics↗

bioRxiv2020

Heterochromatin flexibility contributes to chromosome segregation in cell nucleus

While there is a prevalent genome organization in eukaryotic cells, with heterochromatin concentrated at the nuclear periphery, anomalous cases do occur. Deviations of chromatin distribution are frequent, for example, upon aging, under malignant diseases, or even naturally in rod cells of nocturnal mammals. Using molecular dynamic simulations, we study the segregation of heterochromatin in the cell nucleus by modeling interphase chromosomes as diblock ring copolymers confined in a rigid spherical shell. In our model, heterochromatin and euchromatin are distinguished by their bending stiffnesses, while an interaction potential between the spherical shell and chromatin is used as a proxy for lamin-associated proteins. Our simulations indicate that in the absence of attractive interactions between the nuclear shell and the chromatin, the majority of heterochromatin segregates towards the nuclear interior due to depletion of less flexible heterochromatin segments from the nuclear periphery. This inverted chromatin distribution is in accord with experimental observations in rod cells. This "inversion" is also found to be independent of the heterochromatin concentration and chromosome number, and is further enhanced by additional attractive interactions between heterochromatin segments. as well as by allowing bond-crossing to emulate topoisomerase activity. The usual chromatin distribution, with heterochromatin at the periphery, can be recovered by further increasing the bending stiffness of heterochromatin segments or by turning on attractive interactions between the nuclear shell and heterochromatin. Overall, our results indicate that bending stiffness of chromatin could be a contributor to chromosome organization along with differential effects of HP1-driven phase segregation and of loop extruders, and interactions with the nuclear envelope and topological constraints.

biophysics↗

bioRxiv2018

Receptor-ligand rebinding kinetics in confinement

Rebinding kinetics of molecular ligands plays a critical role in biomachinery, from regulatory networks to protein transcription, and is also a key factor for designing drugs and high-precision biosensors. In this study, we investigate initial release and rebinding of ligands to their binding sites grafted on a planar surface, a situation commonly observed in single molecule experiments and which occurs during exocytosis in vivo. Via scaling arguments and molecular dynamic simulations, we analyze the dependence of non-equilibrium rebinding kinetics on two intrinsic length scales: average separation distance between the binding sites and dimensions of diffusion volume (e.g., height of the experimental reservoir in which diffusion takes place or average distance between receptor-bearing surfaces). We obtain time-dependent scaling laws for on rates and for the cumulative number of rebinding events (the time integral of on rates) for various regimes. Our analyses reveal that, for diffusion-limited cases, the on rate decreases via multiple power law regimes prior to the terminal steady-state regime, in which the on rate becomes constant. At intermediate times, at which particle density has not yet become uniform throughout the reservoir, the number of rebindings exhibits a distinct plateau regime due to the three dimensional escape process of ligands from their binding sites. The duration of this regime depends on the average separation distance between binding sites. Following the three-dimensional diffusive escape process, a one-dimensional diffusive regime describes on rates. In the reaction-limited scenario, ligands with higher affinity to their binding sites (e.g., longer residence times) delay the power laws. Our results can be useful for extracting hidden time scales in experiments where kinetic rates for ligand-receptor interactions are measured in microchannels, as well as for cell signaling via diffusing molecules.

biophysics↗

bioRxiv2017

Facilitated Dissociation Of Transcription Factors From Single DNA Binding Sites

The binding of transcription factors (TFs) to DNA controls most aspects of cellular function, making the understanding of their binding kinetics imperative. The standard description of bimolecular interactions posits TF off-rates are independent of TF concentration in solution. However, recent observations have revealed that proteins in solution can accelerate the dissociation of DNA-bound proteins. To study the molecular basis of facilitated dissociation (FD), we have used single-molecule imaging to measure dissociation kinetics of Fis, a key E. coli TF and major bacterial nucleoid protein, from single dsDNA binding sites. We observe a strong FD effect characterized by an exchange rate {bsim}1 x 104 M-1s-1, establishing that FD of Fis occurs at the single-binding-site level, and we find that the off-rate saturates at large Fis concentrations in solution. While spontaneous (i.e., competitor-free) dissociation shows a strong salt dependence, we find that facilitated dissociation depends only weakly on salt. These results are quantitatively explained by a model in which partially dissociated bound proteins are susceptible to invasion by competitor proteins in solution. We also report FD of NHP6A, a yeast TF whose structure differs significantly from Fis. We further perform molecular dynamics simulations, which indicate that FD can occur for molecules that interact far more weakly than those we have studied. Taken together, our results indicate that FD is a general mechanism assisting in the local removal of TFs from their binding sites and does not necessarily require cooperativity, clustering, or binding site overlap.\n\nSIGNIFICANCE STATEMENTTranscription factors (TFs) control biological processes by binding and unbinding to DNA. Therefore it is crucial to understand the mechanisms that affect TF binding kinetics. Recent studies challenge the standard picture of TF binding kinetics by demonstrating cases of proteins in solution accelerating TF dissociation rates through a facilitated dissociation (FD) process. Our study shows that FD can occur at the level of single binding sites, without the action of large protein clusters or long DNA segments. Our results quantitatively support a model of FD in which competitor proteins invade partially dissociated states of DNA-bound TFs. FD is expected to be a general mechanism for modulating gene expression by altering the occupancy of TFs on the genome.\n\nAuthor ContributionsRamsey I. Kamar\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper\n\nEdward J. Banigan\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper\n\nAykut Erbas\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper\n\nRebecca D. Giuntoli\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper\n\nMonica Olvera de la Cruz\n\ndesigned research, performed research, wrote the paper\n\nReid C. Johnson\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper\n\nJohn F. Marko\n\ndesigned research, performed research, contributed new reagents/analytic tools, analyzed data, wrote the paper

biophysics↗