PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.24.353243v1?rss=1

Authors: Rani, G., Kuroda, K., Vemparala, S.

Abstract:

Using atomistic molecular dynamics simulations, we study the interaction of ternary methacrylate polymers, composed of charged cationic, hydrophobic and neutral polar groups, with model bacterial membrane. Our simulation data shows that the random ternary polymers can penetrate deep into the membrane interior and partitioning of even a single polymer has a pronounced effect on the membrane structure. Lipid reorganization, on polymer binding, shows a strong affinity of the ternary polymer for anionic POPG lipids and the same is compared with the control case of binary polymers (only cationic and hydrophobic groups). While binary polymers exhibit strong propensity of acquired amphiphilic conformations upon membrane insertion, our results strongly suggest that such amphiphilic conformations are absent in the case of random ternary polymers. The ternary polymers adopt a more folded conformation, staying aligned in the direction of the membrane normal and subsequently penetrating deeper into the membrane interior suggesting a novel membrane partitioning mechanism without amphiphilic conformations. Finally, we also examine the interactions of ternary polymer aggregates with model bacterial membranes, which show that replacing some of the hydrophobic groups by polar groups leads to weakly held ternary aggregates enabling them to undergo rapid partitioning and insertion into membrane interior. Our work thus underscores the role of inclusion of polar groups into the framework of traditional binary biomimetic antimicrobial polymers and suggests different mode of partitioning into bacterial membranes, mimicking antimicrobial mechanism of globular antimicrobial peptides like Defensin.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.23.338079v1?rss=1

Authors: Bajpai, G., Amiad-Pavlov, D., Lorber, D., Volk, T., Safran, S.

Abstract:

Intact-organism imaging of Drosophila larvae reveals and quantifies chromatin-aqueous phase separation. The chromatin can be organized near the lamina layer of the nuclear envelope, conventionally fill the nucleus, be organized centrally, or as a wetting droplet. These transitions are controlled by changes in nuclear volume and the interaction of chromatin with the lamina (part of the nuclear envelope) at the nuclear periphery. Using a simple polymeric model that includes the key features of chromatin self-attraction and its binding to the lamina, we demonstrate theoretically that it is the competition of these two effects that determines the mode of chromatin distribution. The qualitative trends as well as the compositional profiles obtained in our simulations compare well with the observed intact-organism imaging and quantification. Since the simulations contain only a small number of physical variables we can identify the generic mechanisms underlying the changes in the observed phase separations.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.23.352641v1?rss=1

Authors: Dalwadi, M. P., Pearce, P.

Abstract:

Bacteria use intercellular signaling, or quorum sensing (QS), to share information and respond collectively to aspects of their surroundings. The autoinducers that carry this information are exposed to the external environment; consequently, they are affected by factors such as removal through fluid flow, a ubiquitous feature of bacterial habitats ranging from the gut and lungs to lakes and oceans. To understand how QS genetic architectures in cells promote appropriate population-level phenotypes throughout the bacterial life cycle requires knowledge of how these architectures determine the QS response in realistic spatiotemporally varying flow conditions. Here, we develop and apply a general theory that identifies and quantifies the conditions required for QS activation in fluid flow by systematically linking cell- and population-level genetic and physical processes. We predict that, when a subset of the population meets these conditions, cell-level positive feedback promotes a robust collective response by overcoming flow-induced autoinducer concentration gradients. By accounting for a dynamic flow in our theory, we predict that positive feedback in cells acts as a low-pass filter at the population level in oscillatory flow, allowing a population to respond only to changes in flow that occur over slow enough timescales. Our theory is readily extendable, and provides a framework for assessing the functional roles of diverse QS network architectures in realistic flow conditions.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.22.349084v1?rss=1

Authors: Senra, D., Paez, A., Gueron, G., Bruno, L., Guisoni, N.

Abstract:

Filopodia are actin-built finger-like dynamic structures that protrude from the cell cortex. These structures can sense the environment and play key roles in migration and cell-cell interactions. The growth-retraction cycle of filopodia is a complex process exquisitely regulated by intra- and extra-cellular cues, whose nature remains elusive. Filopodia present wide variation in length, lifetime and growth rate. Here, we investigate the features of filopodia patterns in fixed prostate cancer cells by confocal microscopy. Analysis of almost a thousand filopodia suggests the presence of two different populations: one characterized by a narrow distribution of lengths and the other with a much more variable pattern with very long filopodia. We explore a stochastic model of filopodia growth which takes into account diffusion and reactions involving actin and the regulatory proteins formin and capping, and retrograde flow. Interestingly, we found an inverse dependence between the filopodial length and the retrograde velocity. This result led us to propose that variations in the retrograde velocity could explain the experimental lengths observed for these tumor cells. In this sense, one population involves a wider range of retrograde velocities than the other population, and also includes low values of this velocity. It has been hypothesized that cells would be able to regulate retrograde flow as a mechanism to control filopodia length. Thus, we propound that the experimental filopodia pattern is the result of differential retrograde velocities originated from heterogeneous signaling due to cell-substrate interactions or prior cell-cell contacts.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.22.351395v1?rss=1

Authors: Xiao, J. Y., Hafner, A., Boettiger, A.

Abstract:

Animal genomes are organized into topologically associated domains (TADs), which exhibit more intra-domain than inter-domain contact. However, the absolute difference in contact is usually no more than twofold, even though disruptions to TAD boundaries can change gene expression by 8-10 fold. Existing models fail to explain this superlinear transcriptional response to changes in genomic contact. Here, we propose a futile cycle model where an enzyme stimulated by association with its products can exhibit bistability and hysteresis, allowing a small increase in enhancer-promoter contact to produce a large change in expression without obvious correlation between E-P contact and promoter activity. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile recent global cohesin loop disruption and TAD boundary deletion experiments. We discuss the model in the context of these recent controversial experiments. Together, these analyses advance our interpretation and understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.22.351346v1?rss=1

Authors: Ferro, L. S., Eshun-Wilson, L., Golcuk, M., Fernandes, J., Huijben, T., Gerber, E., Jack, A., Costa, K., Gur, M., Feng, Q., Nogales, E., Yildiz, A.

Abstract:

Microtubule (MT)-associated proteins (MAPs) regulate intracellular transport by selectively recruiting or excluding kinesin and dynein motors from MTs. We used single-molecule and cryo-electron imaging to determine the mechanism of MAP-motor interactions in vitro. Unexpectedly, we found that the regulatory role of a MAP cannot be predicted based on whether it overlaps with the motor binding site or forms liquid condensates on the MT. Although the MT binding domain (MTBD) of MAP7 overlaps with the kinesin-1 binding site, tethering of kinesin-1 by the MAP7 projection domain supersedes this inhibition and results in biphasic regulation of kinesin-1 motility. Conversely, the MTBD of tau inhibits dynein motility without overlapping with the dynein binding site or by forming tau islands on the MT. Our results indicate that MAPs sort intracellular cargos moving in both directions, as neither dynein nor kinesin can walk on a MAP-coated MT without favorably interacting with that MAP.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.23.351841v1?rss=1

Authors: Barta, E.

Abstract:

Deciphering the lactate transport within the uteroplacental unit should be aided by a theoretical model in light of the insurmountable difficulties involved with in-vivo relevant measurements. Here we formulate a boundary value problem that predicts the direction and extent of lactate fluxes within the human placenta under various physiological conditions. It accounts for metabolic processes within the placenta and transporters activity at the two membranes that confine the terminal villi. Lactate concentration inside the terminal villi and its fluxes at the membranes are being computed. Under normal conditions lactate flux from fetal arterioles to the placenta surpasses the flux to the fetus via the umbilical vein. Within the placenta, it adds to the lactate that originates in the glycolysis, some of it degrades to pyruvate and surpluses are delivered to the maternal circulation. The apparent permeabilities of the placental membranes with respect to lactate as well as the specific characterizations of the placental lactate production, hitherto unknown, are being estimated. We determine the range of parameter values that induce sustainable, healthy fetal lactate levels and demonstrate the versatility of lactate exchange between the placenta and the fetus by computing the effect of extreme conditions (e.g., cesarean section, intrauterine growth restriction) on lactate fluxes.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.23.350959v1?rss=1

Authors: Jaddivada, S., Gundiah, N.

Abstract:

Mechanosensitive focal adhesion complexes mediate the dynamic interactions between cells and substrates, and regulate cellular function. Integrins in adhesion complexes link substrate ligands to stress fibers in the cytoskeleton, and aid in load transfer and traction generation during cell adhesion and migration. A repertoire of signaling molecules, including calcium, facilitate this process. We develop a novel one-dimensional, multi-scale, stochastic finite element model of a fibroblast on a substrate which includes calcium signaling, stress fiber remodeling, and focal adhesion dynamics that describes the formation and clustering of integrins to substrate ligands. We link the stochastic dynamics involving motor-clutches at focal adhesions to continuum level stress fiber contractility at various locations along the cell length. The stochastic module links to a calcium signaling module, via IP3 generation, and adaptor protein dyanamics through feedback. We use the model to quantify changes in cellular responses with substrate stiffness, ligand density, and cyclic stretch. Results show that tractions and integrin recruitments vary along the cell length and depend critically on interactions between the stress fiber and reversibly engaging adaptor proteins. Maximum tractions and integrin recruitments were present at the lamellar regions. Cytosolic calcium increased with substrate stiffness and ligand density. The optimal substrate stiffness, based on maximum tractions exerted by the cell, shifted towards stiffer substrates at high ligand densities. Cyclic stretch increased the cytosolic calcium and tractions at lamellipodial and intermediate cell regions. Tractions and integrin recruitments showed biphasic responses with substrate stiffness that increased with ligand density under stretch. The optimal substrate stiffness under stretch shifted towards compliant substrates at a given ligand density. Cells deadhere under stretch, characterized by near-zero recruitments and tractions, beyond a critical substrate stiffness. The coupling of stress fiber contractility to adhesion dynamics is essential in determining cellular responses under external mechanical perturbations.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.22.349522v1?rss=1

Authors: Marquez-Miranda, V., Rojas, M., Duarte, Y., Diaz-Franulic, I., Holmgren, M., Cachau, R., Gonzalez-Nilo, F. D.

Abstract:

SARS-CoV-2 ORF3a is believed to form ion channels, which may be involved in the modulation of virus release, and has been implicated in various cellular processes like the up-regulation of fibrinogen expression in lung epithelial cells, downregulation of type 1 interferon receptor, caspase-dependent apoptosis, and increasing IFNAR1 ubiquitination. ORF3a assemblies as homotetramers, which are stabilized by residue C133. A recent cryoEM structure of a homodimeric complex of ORF3a has been released. A lower-resolution cryoEM map of the tetramer suggests two dimers form it, arranged side by side. The dimer's cryoEM structure revealed that each protomer contains three transmembrane helices arranged in a clockwise configuration forming a six helices transmembrane domain. This domain's potential permeation pathway has six constrictions narrowing to about 0.1 nm in radius, suggesting the structure solved is in a closed or inactivated state. At the cytosol end, the permeation pathway encounters a large and polar cavity formed by multiple beta strands from both protomers, which opens to the cytosolic milieu. We modeled the tetramer following the arrangement suggested by the low-resolution tetramer cryoEM map. Molecular dynamics simulations of the tetramer embedded in a membrane and solvated with 0.5 M of KCl were performed. Our simulations show the cytosolic cavity is quickly populated by both K+ and Cl-, yet with different dynamics. K+ ions moved relatively free inside the cavity without forming proper coordination sites. In contrast, Cl- ions enter the cavity, and three of them can become stably coordinated near the intracellular entrance of the potential permeation pathway by an inter-subunit network of positively charged amino acids. Consequently, the central cavity's electrostatic potential changed from being entirely positive at the beginning of the simulation to more electronegative at the end.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.22.351130v1?rss=1

Authors: Liese, S., Carlson, A.

Abstract:

The steric repulsion between proteins on biological membranes is one of the most generic mechanisms that cause membrane shape changes. We present a minimal model where a spontaneous curvature is induced by steric repul- sion between membrane-associated proteins. Our results show that the interplay between the induced spontaneous curvature and the membrane tension determine the energy minimizing shapes, which describe the wide range of experimentally observed membrane shapes, i.e. flat membranes, spherical vesicles, elongated tubular protrusions, and pearling structures. Moreover, the model gives precise predictions on how membrane shape changes by protein crowding can be tuned by controlling the protein size, the density of proteins and the size of the crowded domain.

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