PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.18.388843v1?rss=1

Authors: Van Oort, C. M., Ferrell, J. B., Remington, J. M., Wshah, S., Li, J.

Abstract:

Antibiotic resistance is a critical public health problem. Each year ${sim}2.8$ million resistant infections lead to more than 35,000 deaths in the U.S. alone. Anti-microbial peptides (AMPs) show promise in treating resistant infections. But, applications of known AMPs have encountered issues in development, production, and shelf-life. To drive the development of AMP-based treatments it is necessary to create design approaches with higher precision and selectivity towards resistant targets. In this paper we present AMPGAN v2, a generative adversarial network (GAN) based approach for rational AMP design. Like AMPGAN, AMPGAN v2 combines data driven priors and controlled generation. These elements allow for the generation of AMP candidates tailored for specific applications. AMPGAN v2 is able to generate AMP candidates that are novel and diverse, making it an efficient AMP design tool.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.18.388561v1?rss=1

Authors: Medina, L., Gonzalez Lizarraga, F., Dominguez Meijide, A., Ploper, D., Parrales, V., Sequeira, S., Cima Omorri, M. S., Zweckstetter, M., del Bel, E., Michel, P. P., Fleming Outeiro, T., Raisman-Vozari, R., Chehin, R. N., Socias, S. B.

Abstract:

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts alpha-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.18.388066v1?rss=1

Authors: Longhan, X., Wang, Z., Huang, G., Liu, B., Zhou, Z., Liang, B., Liu, Y.

Abstract:

Lower limb assistive robots have a wide range of applications in medical rehabilitation, hiking, and the military. The purpose of this work is to investigate the efficiency of wearable assistive devices under different weight-bearing walking conditions. We designed an experimental platform, with a lightweight ankle-assisted robot weighing 5.2 kg and carried mainly on the back. Eight subjects were tested in three experimental conditions: free walk with load (FWL), power-off with load (POFL), and power-on with load (PONF) for different levels of force at a walking speed of 3.6 km/h. We recorded the metabolic expenditure and kinematics of the subjects under three levels of weight-bearing (equal to 10%, 20%, and 30% of body mass). The critical forces from the fit of the assistive force and metabolic depletion curves were 130 N, 160 N and 215 N at three different load levels. The intrinsic weight of our device increases mechanical work at the ankle as the load weight rises, with 2.08 J, 2.43 J, 2.73 J for one leg during a gait cycle. The ratio of the mechanical work input by the robot to the mechanical work output by the weight of the device decreases (0.904, 0.717, and 0.513 with different load carriages), verifying that the walking assistance efficiency of such devices decreases as the weight rises. In terms of mechanical work in the ankle joint, our results confirm that the efficiency of the ankle-assisted walking robot decreases as weight bearing increases, which provides important guidance for the lightweight design of portable weight-bearing walking robots.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.19.390179v1?rss=1

Authors: Pohorille, A., Wei, C.

Abstract:

To understand the transition from inanimate matter to life, we studied a process that directly couples simple metabolism to evolution via natural selection, demonstrated experimentally by Adamala and Szostak (Nat. Chem. 2013, 5, 495-501). In this process, dipeptides synthesized inside precursors of cells promote absorption of fatty acid micelles to vesicles inducing their preferential growth and division at the expense of other vesicles. The process is explained on the basis of coarse-grained molecular dynamics simulations, each extending for tens of microseconds, carried out to model fusion between a micelle and a membrane, both made of fatty acids in the absence and presence of hydrophobic dipeptides. In all systems with dipeptides, but not in their absence, fusion events were observed. They involve the formation of a stalk made by hydrophobic chains from the micelle and the membrane, similar to that postulated for vesicle-vesicle fusion. The emergence of a stalk is facilitated by transient clusters of dipeptides, side chains of which formed hydrophobic patches at the membrane surface. Committor probability calculations indicate that the size of a patch is a suitable reaction coordinate and allow for identifying the transition state for fusion. Free energy barrier to fusion is greatly reduced in the presence of dipeptides to only 4-5 kcal/mol, depending of the hydrophobicity of side chains. The mechanism of mediated fusion, which is expected to apply to other small peptides and hydrophobic molecules, provides a robust means by which a nascent metabolism can confer evolutionary advantage to precursors of cells.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.19.390161v1?rss=1

Authors: Jonely, M., Singh, R. K., Bass, B., Noriega, R.

Abstract:

Drosophila melanogaster Dicer-2 is a large, multidomain protein that cleaves double-stranded RNA (dsRNA) into small interfering RNAs in a terminus-dependent manner as part of the RNA interference pathway. We characterize the local binding environment involved in this substrate-selective molecular recognition event by monitoring the time-resolved photophysics of a cyanine dye linked to the dsRNA terminus. We observe substantial changes in the molecular rigidity and local freedom of motion of the probe as a function of distinct conformations of the biomolecular complex between Dicer-2 and dsRNA as a function of dsRNA termini, the presence of regulatory proteins, and the addition of a biochemical energy source (ATP) or a non-hydrolysable equivalent (ATP-{gamma}S). With a clustering analysis based solely on these molecular-scale measures of the local binding environment at the dsRNA terminus, we identify sub-populations of similar conformations that define distinct modes of molecular recognition which are correlated with biochemical activity. These observations reveal the important role of substrate-selective molecular recognition properties for proteins with multiple domains that can bind RNA, regulatory proteins, and cofactors.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.18.388447v1?rss=1

Authors: Anselmi, M., Hub, J. S.

Abstract:

SHP2 is a critical regulator of signal transduction implicated in developmental disorders and cancer. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as a key "allosteric switch" for SHP2 activation. We critically review structural data and use extensive molecular simulations to test the "allosteric switch" model of activation. However, we find that the binding cleft in N-SH2 is constitutively flexible and open in solution, and that a closed cleft found in certain structures has been imposed by crystal contacts. The free energy cost for N-SH2 release is only marginally influenced by the binding cleft. We conclude that not the N-SH2 binding cleft but instead the opening of a central {beta}-sheet of N-SH2 is the key allosteric switch triggering SHP2 activation.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.19.384313v1?rss=1

Authors: Mazal, H. A., Iljina, M., Riven, I., Haran, G.

Abstract:

AAA+ ring-shaped machines, such as ClpB and Hsp104, mediate substrate translocation through their central channel by a set of pore loops. Recent structural studies suggested a universal hand-over-hand translocation mechanism, in which pore loops are moving rigidly in tandem with their corresponding subunits. However, functional and biophysical studies are in discord with this model. Here, we directly measure the real-time dynamics of the pore loops of ClpB and their response to substrate binding, using single-molecule FRET spectroscopy. All pore loops undergo large-amplitude fluctuations on the microsecond timescale, and change their conformation upon interaction with substrate proteins. Pore-loop conformational dynamics are modulated by nucleotides and strongly correlate with disaggregation activity. The differential behavior of the pore loops along the axial channel points to a fast Brownian-ratchet translocation mechanism, which likely acts in parallel to the much slower hand-over-hand process.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.19.389775v1?rss=1

Authors: Uematsu, M., Shimizu, T., Shindou, H.

Abstract:

The physical properties of lipids, such as viscosity, are homeostatically maintained in cells, and are intimately involved in physiological roles. Measurement of the physical properties of plasma membranes has been achieved primarily through chemical or genetically encoded fluorescent probes, however, the effect of the probes themselves on these physical properties hampered accurate measurements. In addition, as most probes target plasma membranes, physical properties of lipids in intracellular organelles, including lipid droplets (LDs) are yet to be analyzed. Here, we present a novel Raman microscopy-based approach for quantifying the intracellular physical properties of lipids under deuterium-labeled fatty acid treatment conditions. Focusing on the fact that Raman spectra of carbon-deuterium vibration are altered depending on the surrounding lipid species, we quantitatively represented the physical properties of lipids as the gauche/trans conformational ratio of the introduced labeled fatty acids, which can be used as an indicator of viscosity. Intracellular Raman imaging revealed that the gauche/trans ratio of cytosolic regions was robustly preserved against stimuli attempting to alter the lipid composition. This was likely due to LDs functioning as a buffer against excess gauche/trans ratio. The novel approach, that is, using the target lipid itself as a probe, overcomes the issues presented by conventional probes, making it useful for the quantitative evaluation of biological functions and regulatory mechanisms associated with the physical state of intracellular lipid environments.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.19.389494v1?rss=1

Authors: Shan, Y., Zhang, X., Song, C., Liu, Y., Ke, P., Kuo, Y.-C., Wang, Y.

Abstract:

Plexins are semaphorin receptors that play essential roles in neuronal axon guidance and in many other important biological processes. Plexin signaling depends on a semaphorin-induced dimerization mechanism, and is modulated by small signaling GTPases of the Rho family, of which RND1 serves as a plexin activator yet its close homolog RhoD an inhibitor. Using molecular dynamics (MD) simulations we showed that RND1 reinforces plexin dimerization interface whereas RhoD destabilizes it due to their differential interaction with cell membrane. Upon binding plexin dimers at the Rho-GTPase binding (RBD) domains, RND1 and RhoD interact differently with the inner leaflet of cell membrane, and exert opposite effects on the dimerization interface via an allosteric network involving the RBD domain, RBD linkers, and a buttress segment adjacent to the dimerization interface. The differential membrane interaction is attributed to the fact that, unlike RND1, RhoD features a short C-terminal tail and a positively-charged membrane interface.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.11.17.383745v1?rss=1

Authors: Reyes-Aldrete, E., Dill, E., Bussetta, C., Szymanski, M. R., Diemer, G. S., Maindola, P., White, M., Choi, K., Morais, M.

Abstract:

Double-stranded DNA viruses package their genomes into pre-assembled protein procapsids. This process is driven by macromolecular motors that transiently assemble at a unique vertex of the procapsid and utilize homomeric ring ATPases to couple genome encapsidation to ATP hydrolysis. Here we describe biochemical and biophysical characterization of the packaging ATPase from Lactococcus lactis phage ascc{varphi}28. Size-exclusion chromatography, analytical ultracentrifugation, small angle x-ray scattering, and negative stain TEM indicate that the ~45 kDa protein formed a 443 kDa cylindrical assembly with a maximum dimension of ~155 Angstroms and radius of gyration of ~54 Angstroms. Together with the dimensions of the crystallographic asymmetric unit from preliminary X-ray diffraction experiments, these results indicate that gp11 forms a decameric D5-symmetric complex consisting of two pentameric rings related by 2-fold symmetry. Additional kinetic analysis shows that recombinantly expressed gp11 has ATPase activity comparable to that of functional ATPase rings assembled on procapsids in other genome packaging systems. Hence, gp11 forms rings in solution that likely reflect the fully assembled ATPases in active virus-bound motor complexes. Whereas ATPase functionality in other dsDNA phage packaging systems requires assembly on viral capsids, the ability to form functional rings in solution imparts gp11 with significant advantages for high resolution structural studies and rigorous biophysical/biochemical analysis.

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