PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.12.333252v1?rss=1

Authors: Malik, A., Pande, K., Kumar, A., Vemula, A., Rottela, M., Chandramohan, V.

Abstract:

COP9 Signalosome Subunit 2 is a highly conserved multiprotein complex which is involved in the cellular process and developmental process. It is one of the essential components in the COP9 Signalosome Complex (CSN). It is also involved in neuronal differentiation interacting with NIF3L1. The gene involved in neuronal differentiation is negatively regulated due to the transcription co-repressor interaction of NIF3L1 with COPS2. In the present study, we have evaluated the outcome for 90 non-synonymous single nucleotide polymorphisms (nsSNPs) in COPS2 gene through computational tools. After the analysis, 4 SNPs (S120C, N144S, Y159H, R173C) were found to be deleterious. The native and mutated structures were prepared using discovery studio and docked to check the interactions with NIF3L1.On the basis of ZDOCK score the top 3 mutations (N144S, Y159H, R173C) were screened out. Further to analyze the effect of amino acid substitution on the molecular structure of protein Molecular Dynamics simulation was carried out. Analysis based on RMSD, RMSF, RG, H-bond showed a significant deviation in the graph, which demonstrated conformation change and instability compared to the wild structure. As it is known mutations in COPS2 gene can disrupt the normal activity of the CSN2 protein which may cause neuronal differentiation. Our results showed N144S, Y159H and R173C mutations are to be more pathogenic and may cause disease.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.11.335299v1?rss=1

Authors: Gobeil, S., Janowska, K., McDowell, S., Mansouri, K., Parks, R., Manne, K., Stalls, V., Kopp, M., Henderson, R., Edwards, R. J., Haynes, B. F., Acharya, P.

Abstract:

The SARS-CoV-2 spike (S) protein is the target of vaccine design efforts to end the COVID-19 pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic, and are now the dominant form worldwide. Here, we analyze the D614G mutation in the context of a soluble S ectodomain construct. Cryo-EM structures, antigenicity and proteolysis experiments suggest altered conformational dynamics resulting in enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the conformational dynamics of the Receptor Binding Domains (RBD) in the G614 S ectodomain, demonstrating an allosteric effect on the RBD dynamics triggered by changes in the SD2 region, that harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 spike conformational dynamics and allostery, and have implications for vaccine design.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.12.336016v1?rss=1

Authors: Ni, D., Lau, K., Lehmann, F., Fraenkli, A., Hacker, D., Pojer, F., Stahlberg, H.

Abstract:

The human membrane protein Angiotensin-converting enzyme 2 (hACE2) acts as the main receptor for host cells invasion of the new coronavirus SARS-CoV-2. The viral surface glycoprotein Spike binds to hACE2, which triggers virus entry into cells. As of today, the role of hACE2 for virus fusion is not well understood. Blocking the transition of Spike from its prefusion to post-fusion state might be a strategy to prevent or treat COVID-19. Here we report a single particle cryo-electron microscopy analysis of SARS-CoV-2 trimeric Spike in presence of the human ACE2 ectodomain. The binding of purified hACE2 ectodomain to Spike induces the disassembly of the trimeric form of Spike and a structural rearrangement of its S1 domain to form a stable, monomeric complex with hACE2. This observed hACE2 dependent dissociation of the Spike trimer suggests a mechanism for the therapeutic role of recombinant soluble hACE2 for treatment of COVID-19.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.11.334979v1?rss=1

Authors: Mondal, A., Dolui, S., Dhabal, S., Bhattacharjee, A., Maiti, N. C.

Abstract:

Parkinson disease (PD) is linked to alpha-synuclein (aS) aggregation and deposition of amyloid in the substantia nigra region of the brain tissues. Recent reports suggested that oligomeric assembly structure could be neurotoxic to neuronal cells. In the current investigation we produced two distinct classes of aS oligomers and link the protein conformation state and stability to neuronal cell toxicity. Natural oligomers (NO) enriched with alpha-helical folds are produced in storage of aS at below -20{degrees}C for 7 days. Induced oligomer (IO), often observed in the aggregation pathway of aS were made incubating the protein solution at 37 {degrees}C. Natural oligomers remained stable and did not transform into beta-sheet rich amyloid fiber and exhibited higher toxicity (80% cell death) compared to induced oligomers. Natural oligomers were ovular shape and the size ranged between 4-5.5 nm. It maintained significant number (~ 60%) of residues in alpha-helical conformational space. However, initiation of hydrophobic zipping with beta sheet conformation was evidenced in induced oligomer (IO) and a lesser number residues (45%) remained with preference to alpha-helical secondary structure. Hydrophobic collapse leads the transformation of IO into thermodynamically most stable beta-sheet rich amyloid fibril. Molten globule like secondary structure stabilized by H-bonding in natural oligomers caused enhanced stability and cellular toxicity compared to induced oligomer. Thus off-pathway/natural oligomers could be plausible reason of neuronal cell death and possible cause of Parkinson disease.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.11.335042v1?rss=1

Authors: Sarkar, S., Choubey, S.

Abstract:

Inter and intra-cellular signaling are essential for individual cells to execute various physiological tasks and accurately respond to changes in their environment. Signaling is carried out via diffusible molecules, the transport of which is often aided by active processes that provide directional advection. How diffusion and advection together impact the accuracy of information transmission during cell signaling remains less studied. To this end, we study a one-dimensional model of cell signaling and compute the mutual information (MI) as a measure of information transmission. We find that the efficacy of the information transmission improves with advection only when the system parameters result in Peclet number greater than one. Intriguingly, MI exhibits nontrivial scaling with the Peclet number, characterized by three distinct regimes. We demonstrate that the observed dependence of MI on the transport properties of signaling molecules has important consequences on cellular communication.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.10.334474v1?rss=1

Authors: Rudnizky, S., Khamis, H., Ginosar, Y., Goren, E., Melamed, P., Kaplan, A.

Abstract:

Chromatosomes, composed of nucleosomes and linker histones, play a fundamental role in chromatin regulation. However, a detailed understanding of their structure is lacking, partially due to their complex dynamics. Using single-molecule DNA unzipping with optical tweezers to map histone-DNA interactions in the chromatosome, we reveal a symmetrical compaction of the nucleosome core, governed by the linker histone globular domain contacts at the dyad. Dynamic mapping revealed that the C-terminal domain binds both DNA linkers, at ~ {+/-}115 and ~ {+/-}140 bp from the dyad, to compact the nucleosome entry and exit. Although H1 interacts more transiently with one linker, these dynamic contacts are crucial for stabilizing the binding to the second one. Extensive unzipping of the linker DNA, which mimics its invasion by motor proteins, shifts H1 off the dyad, triggering nucleosome decompaction. Our findings reveal molecular details of chromatosome compaction and its potential modulation by the transcription machinery.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.10.334441v1?rss=1

Authors: Benayad, Z., von Bülow, S., Stelzl, L. S., Hummer, G.

Abstract:

Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of c{approx}0.6, FUS LCD condensation is observed, where =1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor =0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01-0.4 mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001-0.02 Pa s for the FUS LCD droplets with scaling factors in the range of 0.625-0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.06.328252v1?rss=1

Authors: Dolega, M., Monnier, S., Brunel, B., Joanny, J.-F., Recho, P., Cappello, G.

Abstract:

Imposed deformations play an important role in morphogenesis and tissue homeostasis, both in normal and pathological conditions. To perceive mechanical perturbations of different types and magnitudes, tissues need appropriate detectors, with a compliance that matches the perturbation amplitude. By comparing results of selective osmotic compressions of cells within multicellular aggregates with small osmolites and global aggregate compressions with big osmolites, we show that global compressions have a strong impact on the aggregates growth and internal cell motility, while selective compressions of same magnitude have almost no effect. Both compressions alter the volume of individual cells in the same way but, by draining the water out of the extracellular matrix, the global one imposes a residual compressive mechanical stress on the cells while the selective one does not. We conclude that, in aggregates, the extracellular matrix is as a sensor which mechanically regulates cell proliferation and migration in a 3D environment.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.09.333203v1?rss=1

Authors: Weissenbruch, K., Grewe, J., Stricker, K., Baulesch, L., Schwarz, U. S., Bastmeyer, M.

Abstract:

Nonmuscle myosin II (NM II) is an integral part of essential cellular processes, including adhesion and migration. Mammalian cells express up to three isoforms termed NM IIA, B, and C. We used U2OS cells to create CRISPR/Cas9-based knockouts of all three isoforms and analyzed the phenotypes on homogeneous and micropatterned substrates. We find that NM IIA is essential to build up cellular tension during initial stages of force generation, while NM IIB is necessary to elastically stabilize NM IIA-generated tension. The knockout of NM IIC has no detectable effects. A scale-bridging mathematical model explains our observations by relating actin fiber stability to the molecular rates of the myosin crossbridge cycle. We also find that NM IIA initiates and guides co-assembly of NM IIB into heterotypic minifilaments. We finally use mathematical modeling to explain the different exchange dynamics of NM IIA and B in minifilaments, as measured in FRAP experiments.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.09.331009v1?rss=1

Authors: Bajpai, S., Prabhakar, R., Chelakkot, R., Inamdar, M. M.

Abstract:

A key challenge in biology is to understand how spatiotemporal patterns and structures arise during the development of an organism. An initial aggregate of spatially uniform cells develops and forms the differentiated structures of a fully developed organism. On the one hand, contact-dependent cell-cell signalling is responsible for generating a large number of complex, self-organized, spatial patterns in the distribution of the signalling molecules. On the other hand, the motility of cells coupled with their polarity can independently lead to collective motion patterns that depend on mechanical parameters influencing tissue deformation, such as cellular elasticity, cell-cell adhesion and active forces generated by actin and myosin dynamics. Although modelling efforts have, thus far, treated cell motility and cell-cell signalling separately, experiments in recent years suggest that these processes could be tightly coupled. Hence, in this paper, we study how the dynamics of cell polarity and migration influence the spatiotemporal patterning of signalling molecules. Such signalling interactions can occur only between cells that are in physical contact, either directly at the junctions of adjacent cells or through cellular protrusional contacts. We present a vertex model which accounts for contact-dependent signalling between adjacent cells and between non-adjacent neighbours through long protrusional contacts that occur along the orientation of cell polarization. We observe a rich variety of spatiotemporal patterns of signalling molecules that is influenced by polarity dynamics of the cells, relative strengths of adjacent and non-adjacent signalling interactions, range of polarized interaction, signalling activation threshold, relative time scales of signalling and polarity orientation, and cell motility. Though our results are developed in the context of Delta-Notch signalling, they are sufficiently general and can be extended to other contact dependent morpho-mechanical dynamics.

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