PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.290643v1?rss=1

Authors: Vasista, A., Mandal, B., Anki Reddy, K.

Abstract:

The most common age-related neurodegenerative disorder, Alzheimer's disease, is clinically characterized by continuous neuronal loss resulting in loss of memory and dementia with no cure to date. Amyloid- {beta}(A{beta}) aggregates and tau protein are believed to be the causative agents of this pathogenesis. In the present study, we have investigated the effect of the Pro-Drug peptide (PDp) and its metabolites (-aspartyl & {beta}-aspartyl) on the A{beta} aggregates using atomistic molecular dynamics simulations. One of the key findings in our work is in the presence of -aspartyl as a ligand, the salt bridges which hold the N-terminals together are completely disrupted, thus setting the N-terminals free and exposed entirely to the solvent which can make the aggregation of A{beta} less severe. The efficiency of the ligands, which are responsible for the disruption of A{beta}, depends on the alignment and strength of the repulsive interactions. Besides repulsive interactions, we found that there is a need for hydrogen bonding, which acts as a support for the ligand to stay in the vicinity of the aggregate. Moreover, we have noticed that one of the metabolites, namely {beta}-aspartyl, formed more hydrogen bonds with the aggregate than the other ligands and had a different mode of action with the chains of A{beta} due to its unique flexible kink in the backbone.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.10.291757v1?rss=1

Authors: Delgado, J. M., Duro, N., Rogers, D. M., Tkatchenko, A., Pandit, S. A., Varma, S.

Abstract:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2's higher infectivity may lie in its host receptor recognition mechanism. This is because experiments show that the human ACE2 protein, which serves as the primary receptor for both CoVs, binds to CoV-2's spike protein 5-20 fold stronger than SARS-CoV's spike protein. The molecular basis for this difference in binding affinity, however, remains unexplained and, in fact, a comparison of X-ray structures leads to an opposite proposition. To gain insight, we use all-atom molecular dynamics simulations. Free energy calculations indicate that CoV-2's higher affinity is due primarily to differences in specific spike residues that are local to the spike-ACE2 interface, although there are allosteric effects in binding. Comparative analysis of equilibrium simulations reveals that while both CoV and CoV-2 spike-ACE2 complexes have similar interfacial topologies, CoV-2's spike protein engages in greater numbers, combinatorics and probabilities of hydrogen bonds and salt bridges with ACE2. We attribute CoV-2's higher affinity to these differences in polar contacts, and these findings also highlight the importance of thermal structural fluctuations in spike-ACE2 complexation. We anticipate that these findings will also inform the design of spike-ACE2 peptide blockers that, like in the cases of HIV and Influenza, can serve as antivirals.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.290320v1?rss=1

Authors: Samantray, S., Yin, F., Kav, B., Strodel, B.

Abstract:

The progress towards understanding the molecular basis of Alzheimers's disease is strongly connected to elucidating the early aggregation events of the amyloid-{beta} (A{beta}) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of A{beta} into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the force fields tested can distinguish between aggregation-prone and non-aggregating peptide sequences, producing the same and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as A{beta} were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the A{beta}16-22 peptide and mutations of it as test case. We investigate their performance in modeling the monomeric state, the aggregation into oligomers,and the stability of the aggregation end product, i.e., the fibrillar state. A main finding is that changing the force field has a stronger effect on the simulated aggregation pathway than changing the peptide sequence. Also the new force fields are not able to reproduce the experimental aggregation propensity order of the peptides. Dissecting the various energy contributions shows that AMBER99SB-disp overestimates the interactions between the peptides and water, thereby inhibiting peptide aggregation. More promising results are obtained with CHARMM36m and especially its version with increased protein-water interactions. It is thus recommended to use this force field for peptide aggregation simulations and base future reparameterizations on it.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.290197v1?rss=1

Authors: Li, R., Chen, H., Choi, J. H.

Abstract:

Deployable geometries are finite auxetic structures that preserve their overall shapes during expansion and contraction. The topological behaviors emerge from intricately arranged elements and their connections. Despite considerable utility of such configurations in nature and in engineering, deployable nanostructures have never been demonstrated. Here we show a deployable flight ring, a simplified planar structure of Hoberman sphere, using DNA origami. The DNA flight ring consists of topologically assembled six triangles in two layers that can slide against each other, thereby switching between two distinct (open and closed) states. The origami topology is a trefoil knot, and its auxetic reconfiguration results in negative Poisson ratios. This work shows the feasibility of deployable nanoarchitectures, providing a versatile platform for topological studies and opening new opportunities for bioengineering.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.07.286344v1?rss=1

Authors: Pavlova, A., Lynch, D. L., Daidone, I., Zanetti-Polzi, L., Smith, M. D., Chipot, C., Kneller, D. W., Kovalevsky, A., Coates, L., Golosov, A. A., Dickson, C. J., Velez-Vega, C., Duca, J. S., Vermaas, J. V., Pang, Y. T., Acharya, A., Parks, J. M., Smith, J. C., Gumbart, J. C.

Abstract:

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an -ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N{delta} (HD) and N{epsilon} (HE) protonation of His41 and His164, respectively, the -ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.288571v1?rss=1

Authors: Kosugi, T., Iida, T., Tanabe, M., Iino, R., Koga, N.

Abstract:

Protein complexes exert various functions through allosterically controlled cooperative work. De novo design of allosteric control into protein complexes provides understanding of their working principles and potential tools for synthetic biology. Here, we hypothesized that an allosteric control can be created by restoring lost functions of pseudo-enzymes contained as subunits in protein complexes. This was demonstrated by computationally de novo designing ATP binding ability of the pseudo-enzyme subunits in a rotary molecular motor, V1-ATPase. Single molecule experiments with solved crystal structures revealed that the designed V1 is allosterically accelerated than the wild-type by the ATP binding to the created allosteric site and the rate is tunable by modulating the binding affinity. This work opened up an avenue for programming allosteric control into proteins exhibiting concerted functions.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.08.285346v1?rss=1

Authors: Lebel, P. M., Dial, R., Vemuri, V. N. P., Garcia, V. E., DeRisi, J., Gomez-Sjoberg, R.

Abstract:

Manual microscopic inspection of fixed and stained blood smears has remained the gold standard for Plasmodium parasitemia analysis for over a century. Unfortunately, smear preparation consumes time and reagents, while manual microscopy is skill-dependent and labor-intensive. Here, we demonstrate that label-free microscopy combined with deep learning enables both life stage classification and accurate parasitemia quantification. Using a custom-built microscope, we find that deep-ultraviolet light enhances image contrast and resolution, achieving four-category classification of Plasmodium falciparum blood stages at an overall accuracy greater than 99%. To increase accessibility, we extended our method to a commercial brightfield microscope using near-ultraviolet and visible light. Both systems were tested extrinsically by parasitemia titration, revealing superior performance over manually-scored Giemsa-stained smears, and a limit of detection below 0.1%. Our results suggest that label-free microscopy combined with deep learning could eliminate the need for conventional blood smear analysis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.287987v1?rss=1

Authors: Durdagi, S., Dag, C., Dogan, B., Yigin, M., Avsar, T., Buyukdag, C., Erol, I., Ertem, F. B., Calis, S., Yildirim, G., Orhan, M., Guven, O., Aksoydan, B., Destan, E., Sahin, K., Besler, S. O., Oktay, L., Shafiei, A., Tolu, I., Ayan, E., Yuksel, B., Peksen, A. B., Gocenler, O., Yucel, A. D., Can, O., Ozabrahamyan, S., Olkan, A., Erdemoglu, E., Aksit, F., Tanisali, G. H., Yefanov, O. M., Barty, A., Tolstikova, A., Ketawala, G. K., Botha, S., Dao, E. H., Hayes, B., Liang, M., Seaberg, M. H., Hunter, M. S., Batyuk, A., Mariani, V., Su, Z., Poitevin, F., Yoon, C. H., Kupitz, C. J., Sierra, R. G., Sn

Abstract:

The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambient-temperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.09.286310v1?rss=1

Authors: Gavins, G., Groeger, K., Bartoscheck, M. D., Wolf, P., Beck-Sickinger, A. G., Bultmann, S., Seitz, O.

Abstract:

DNA nanotechnology is an emerging field, which promises fascinating opportunities for the manipulation and imaging of proteins on a cell surface. The key to progress in the area is the ability to create the nucleic acid-protein junction in the context of living cells. Here we report a covalent labelling reaction, which installs a biostable peptide nucleic acid (PNA) tag. The reaction proceeds within minutes and is specific for proteins carrying a 2 kDa coiled coil peptide tag. Once installed the PNA label serves as a generic landing platform that enables the recruitment of fluorescent dyes via nucleic acid hybridization. We demonstrate the versatility of this approach by recruiting different fluorophores, assembling multiple fluorophores for increased brightness, and achieving reversible labelling by way of toehold mediated strand displacement. Additionally, we show that labelling can be carried out using two different coiled coil systems, with EGFR and ETBR, on both HEK293 and CHO cells. Finally, we apply the method to monitor internalization of EGFR on CHO cells.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.07.286237v1?rss=1

Authors: Swoger, M., Gupta, S., Charrier, E., Bates, M., Hehnly, H., Patteson, A. E.

Abstract:

The ability of cells to take and change shape is a fundamental feature underlying development, wound repair, and tissue maintenance. Central to this process is physical and signaling interactions between the three cytoskeletal polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells sense and respond to the surrounding extracellular matrix is largely unclear. To investigate vimentin's role in substrate sensing, we designed polyacrylamide hydrogels that mimic the elastic and viscoelastic nature of in vivo tissues. Using wild-type and vimentin-null mouse embryonic fibroblasts, we show that vimentin enhances cell spreading on viscoelastic substrates, even though it has little effect in the limit of purely elastic substrates. Our results provide compelling evidence that the vimentin cytoskeletal network is a physical modulator of how cells sense and respond to mechanical properties of their extracellular environment.

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