PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.379230v1?rss=1

Authors: Nakai, T., Ando, T., Goto, T.

Abstract:

Many kinds of peritrichous bacteria that repeat runs and tumbles by using multiple flagella exhibit chemotaxis by sensing a difference in the concentration of the attractant or repellent between two adjacent time points. If a cell senses that the concentration of an attractant has increased, their flagellar motors decrease the switching frequency from counterclockwise to clockwise direction of rotation, which causes a longer run in swimming up the concentration gradient than swimming down. We investigated the turn angle in tumbles of peritrichous bacteria swimming across the concentration gradient of a chemoattractant because the change in the switching frequency in the rotational direction may affect the way tumbles. We tracked several hundreds of runs and tumbles of single Salmonella typhimurium cells in the concentration gradient of L-serine, and found that the turn angle depends on the concentration gradient that the cell senses just before the tumble. The turn angle is biased toward a smaller value when the cells swim up the concentration gradient, whereas the distribution of the angle is almost uniform (random direction) when the cells swim down the gradient. The effect of the observed bias in the turn angle on the degree of chemotaxis was investigated by random walk simulation. In the concentration field where attractants diffuse concentrically from the point source, we found that this angular distribution clearly affects the reduction of the mean square displacement of the cell that has started at the attractant source, that is, the bias in the turn angle distribution contributes to chemotaxis in peritrichous bacteria.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.378828v1?rss=1

Authors: Niemi, A. J., Peng, X.

Abstract:

The spike protein is a most promising target for the development of vaccines and therapeutic drugs against the SARS-CoV-2 infection. But the apparently high rate of mutations makes the development of antiviral inhibitors a challenge. Here a methodology is presented to try and predict mutation hot-spot sites, where a small local change in spike protein's structure can lead to a large scale conformational effect, and change the protein's biological function. The methodology starts with a systematic physics based investigation of the spike protein's C backbone in terms of its local topology. This topological investigation is then combined with a statistical examination of the pertinent backbone fragments; the statistical analysis builds on a comparison with high resolution Protein Data Bank (PDB) structures. Putative mutation hot-spot sites are identified as proximal sites to bifurcation points that can change the local topology of the C backbone in an essential manner. The likely outcome of a mutation, if it indeed occurs, is predicted by a comparison with residues in best-matching PDB fragments together with general stereochemical considerations. The detailed methodology is developed using the already observed D614G mutation as an example. This is a mutation that could have been correctly predicted by the present approach. Several additional examples of potential hot-spot residues are identified and analyzed in detail, some of them are found to be even better candidates for a mutation hot-spot than D614G.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.12.378422v1?rss=1

Authors: Guenther, S., Reinke, P. Y. A., Fernandez-Garcia, Y., Lieske, J., Lane, T. J., Ginn, H., Koua, F., Ehrt, C., Ewert, W., Oberthuer, D., Yefanov, O., Meier, S., Lorenzen, K., Krichel, B., Kopicki, J., Gelisio, L., Brehm, W., Dunkel, I., Seychell, B., Gieseler, H., Norton-Baker, B., Escudero-Perez, B., Domaracky, M., Saouane, S., Tolstikova, A., White, T., Haenle, A., Groessler, M., Fleckenstein, H., Trost, F., Galchenkova, M., Gevorkov, Y., Li, C., Awel, S., Peck, A., Barthelmess, M., Schluenzen, F., Lourdu, X. P., Werner, N., Andaleeb, H., Ullah, N., Falke, S., Srinivasan, V., Franca, B., Schwi

Abstract:

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.10.375105v1?rss=1

Authors: Skrbic, T., Maritan, A., Giacometti, A., Rose, G. D., Banavar, J. R.

Abstract:

The native state structures of globular proteins are stable and well-packed indicating that self-interactions are favored over protein-solvent interactions under folding conditions. We use this as a guiding principle to derive the geometry of the building blocks of protein structures, alpha-helices and strands assembled into beta-sheets, with no adjustable parameters, no amino acid sequence information, and no chemistry. There is an almost perfect fit between the dictates of mathematics and physics and the rules of quantum chemistry. Our theory establishes an energy landscape that channels protein evolution by providing sequence-independent platforms for elaborating sequence-dependent functional diversity. Our work highlights the vital role of discreteness in life and has implications for the creation of artificial life and on the nature of life elsewhere in the cosmos.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.378638v1?rss=1

Authors: Ilangumaran Ponmalar, I., Ayappa, K. G., Basu, J. K.

Abstract:

Developing alternate strategies against pore forming toxin (PFT) mediated bacterial virulence factors require an understanding of the target cellular response to combat rising antimicrobial resistance. Membrane-bound protein complexes involving PFTs, released by virulent bacteria are known to form pores leading to host cell lysis. However, membrane disruption and related lipid mediated active repair processes during attack by PFTs remain largely unexplored. We report counter intuitive and non-monotonic variations in lipid diffusion, measured using confocal fluorescence correlation spectroscopy, due to interplay of lipid ejection and crowding by membrane bound oligomers of a prototypical cholesterol dependent cytolysin, Listeriolysin O (LLO). The observed protein concentration dependent dynamical cross-over is correlated with transitions of LLO oligomeric state populations from rings to arc-like pore complexes, predicted using a proposed two-state free area based diffusion model. At low PFT concentrations, a hitherto unexplored regime of increased lipid diffusivity is attributed to lipid ejection events due to a preponderance of ring-like pore states. At higher protein concentrations where membrane inserted arc-like pores dominate, lipid ejection is less eficient and the ensuing crowding results in a lowering of lipid diffusion. These variations in lipid dynamics are corroborated by macroscopic rheological response measurements of PFT bound vesicles. Our study correlates PFT oligomeric state transitions, membrane remodelling and mechanical property variations, providing unique insights into developing strategies to combat virulent bacterial pathogens responsible for several infectious diseases.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.378026v1?rss=1

Authors: Suvlu, D., Thirumalai, D., Rasaiah, J. C.

Abstract:

Water-mediated interactions (WMIs) play diverse roles in molecular biology. They are particularly relevant in geometrically confined spaces such as the interior of the chaperonin, at the interface between ligands and their binding partners, and in the ribosome tunnel. Inspired in part by the geometry of the ribosome tunnel, we consider confinement effects on the stability of peptides. We describe results from replica exchange molecular dynamics simulations of a system containing a 23-alanine or 23-serine polypeptide confined to non-polar and polar nanotubes in the gas phase and when open to a water reservoir. We quantify the effect of water in determining the preferred conformational states of these polypeptides by calculating the difference in the solvation free energy for the helix and coil states in the open nanotube in the two phases. Our simulations reveal several possibilities. We find that nanoscopic confinement preferentially stabilizes the helical state of polypeptides with hydrophobic side chains, which is explained by the entropic stabilization mechanism proposed on the basis of polymer physics. Polypeptide chains with hydrophilic side chains can adopt helical structures within nanotubes, but helix formation is sensitive to the nature of the nanotube due to WMIs. We elaborate on the potential implications of our findings to the stability of peptides in the ribosome tunnel.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.377200v1?rss=1

Authors: Carlson, M. L., Seyler, S. L., Presse, S.

Abstract:

Bdellovibrio bacteriovorus is a predatory bacterium that preys upon gram-negative bacteria. As such, B. bacteriovorus has the potential to control antibiotic-resistant pathogens and biofilm populations. To survive and reproduce, B. bacteriovorus must locate and infect a host cell. However, in the temporary absence of prey, it is largely unknown how B. bacteriovorus modulate their motility patterns in response to physical or chemical environmental cues to optimize their energy expenditure. To investigate B. bacteriovorus' predation strategy, we track and quantify their motion by measuring speed distributions and velocity autocorrelations as a function of starvation time. An initial unimodal speed distribution, relaxing to that expected for pure diffusion at long times, may be expected. Instead, we observe a complex, non-Brownian, search strategy as evidenced by distinctly bimodal speed distributions. That is, for an increasing amount of time over which B. bacteriovorus is starved, we observe a progressive re-weighting from a fast mode to a slow mode in the speed distribution obtained over consecutive frames. By contrast to its predator, B. bacteriovorus' prey, Escherichia coli exhibits almost immediate decrease to a speed expected from passive diffusion following resuspension from rich to poor media. Distributions of trajectory-averaged speeds for B. bacteriovorus are largely unimodal, indicating nontrivial switching between fast and slow swimming modes within individual observed trajectories rather than there being distinct fast and slow populations. We also find that B. bacteriovorus' slow speed mode is not merely caused by the diffusion of inviable bacteria as subsequent spiking experiments show that bacteria can be resuscitated and bimodality restored. Indeed, starved B. bacteriovorus may modulate the frequency and duration of active swimming as a means of balancing energy consumption and procurement. Our results are evidence of a nontrivial predation strategy, which contrasts with the comparatively simple search pattern of its prey, in response to environmental cues.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.11.378646v1?rss=1

Authors: Lee, W. H., Liu, W., Fan, J.-S., Yang, D.

Abstract:

The viral protease domain (NS3pro) of dengue virus is essential for virus replication and its cofactor NS2B is indispensable for the proteolytic function. Although several NS3pro-NS2B complex structures have been obtained, the dynamic property of the complex remains poorly understood. Using NMR relaxation techniques, here we found that NS3pro-NS2B exists in both closed and open conformations which are in dynamic equilibrium on a sub-millisecond timescale in aqueous solution. Our structural information indicates that the C-terminal region of NS2B is disordered in the open conformation but folded in the closed conformation. Using mutagenesis, we showed that the closed-open conformational equilibrium can be shifted by changing NS2B stability. Moreover, we revealed that the proteolytic activity of NS3pro-NS2B correlates well with the population of the closed conformation. Our results suggest that the closed-open conformational equilibrium can be used by both nature and man to control the replication of dengue virus.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.10.376285v1?rss=1

Authors: Brotzakis, Z. F., Lindstedt, P., Taylor, R., Bernardes, G., Vendruscolo, M.

Abstract:

Tau is a microtubule-associated protein that regulates the stability of microtubules. The affinity of tau for microtubules is modulated by post-translational modifications, and the dysregulation of these events has been associated with the aberrant aggregation of tau in Alzheimer's disease and related tauopathies. Here, we use the metainference cryo- electron microscopy approach to determine an ensemble of structures representing the structure and dynamics of a tau-microtubule complex comprising an extended microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. An analysis of the interactions in these states of structures reveals positions in the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilising effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.10.375493v1?rss=1

Authors: Vander Roest, A. S., Liu, C., Morck, M. M., Kooiker, K. B., Jung, G., Song, D., Dawood, A., Jhingran, A., Pardon, G., Ranjbarvaziri, S., Fajardo, G., Zhao, M., Campbell, K. S., Pruitt, B., Spudich, J. A., Ruppel, K. M., Bernstein, D.

Abstract:

Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1000 mutations, many in {beta}-cardiac myosin (MYH7). Molecular studies of myosin with different HCM mutations have revealed a diversity of effects on ATPase and load-sensitive rate of detachment from actin. It has been difficult to predict how such diverse molecular effects combine to influence forces at the cellular level and further influence cellular phenotypes. This study focused on the P710R mutation that dramatically decreases in vitro motility and actin-activated ATPase, in contrast to other MYH7 mutations. Optical trap measurements of single myosin molecules revealed that this mutation reduced the step size of the myosin motor and the load-sensitivity of the actin detachment rate. Conversely, this mutation destabilized the super-relaxed state in larger, two-headed myosin constructs, freeing more heads to generate force. Micropatterned hiPSC-cardiomyocytes CRISPR-edited with the P710R mutation produced significantly increased force (measured by traction force microscopy) compared with isogenic control cells. The P710R mutation also caused cardiomyocyte hypertrophy and cytoskeletal remodeling, as measured by immunostaining and electron microscopy. Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt. Finally, we used a computational model that integrates measured molecular changes to demonstrate that predicted force traces match the forces measured in cells. These results confirm a key role for regulation of the super-relaxed state in driving hypercontractility in HCM and demonstrate the value of a multiscale approach in revealing key mechanisms of disease.

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