PaperPlayer biorxiv biophysics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.215327v1?rss=1

Authors: Basu, S., Gorai, B., Basu, B., Maiti, P. K.

Abstract:

In experimental research driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.), and to a relatively lesser extent, the biophysical stimulation (electric/magnetic) on the cell-material interaction has been extensively investigated. Considering the central importance of the protein adsorption on cell-material interaction, the role of physiochemical factors on the protein adsorption is also probed. Despite its significance, the quantitative analysis of many such aspects remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation towards modulation of cell functionality on implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on hydroxyapatite, HA (100) surface at 300K using all-atom MD simulation method. Fibronectin adsorption was found to be governed by the attractive electrostatic interaction, which changed with the electric field strength. Non-monotonous changes in structural integrity of fibronectin were recorded with the change in field strength and direction. This can be attributed to the spatial rearrangement of local charges and global structural changes of the protein. The dipole moment vectors of fibronectin, water and HA quantitatively exhibited similar pattern of orienting themselves parallel to the field direction, with field strength dependent increase in their magnitudes. No significant change has been recorded for radial distribution function of water surrounding fibronectin. Field dependent variation in the salt bridge nets and number of hydrogen bonds between fibronectin and hydroxyapatite were also examined. One of the important results in the context of the cell-material interaction is that the RGD sequence of FN was exposed to solvent side, when the field was applied along a direction outward perpendicular to HA (001) surface. Summarizing, the present study provides quantitative insights into the influence of electric field stimulation on biomolecular interactions involved in fibronectin adsorption on hydroxyapatite surface.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.212191v1?rss=1

Authors: Ahmad, R., Kleineberg, C., Su, Y. J., Goli Pozveh, S., Bae, A. J., Bodenschatz, E., Sundmacher, K., Vidakovich-Koch, T., Gholami, A.

Abstract:

Artificial systems capable of self-sustained directed movement are of high interest with respect to development of many challenging applications including medical treatments but also technical applications. The bottom-up assembly of such systems in the context of synthetic biology is still a challenging task. Here, we demonstrate the biocompatibility and efficiency of an artificial light-driven energy module and a motility functional unit by integrating light-switchable photosynthetic vesicles with demembranated flagella, thereby supplying ATP for dynein molecular motors upon illumination. Flagellar propulsion is coupled to its beating frequency and the dynamic synthesis of ATP triggered by energy of light, enabled us to control beating frequency of flagella as a function of illumination. Light-powered functionalized vesicles integrated with different biological building blocks such as bio-polymers and molecular motors may contribute to bottom-up synthesis of artificial cells that are able to undergo motor-driven morphological deformations and exhibit directional motion in a light-controllable fashion.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.212159v1?rss=1

Authors: Mojiri, S., Isbaner, S., Muehle, S., Jang, H., Bae, A. J., Gregor, I., Gholami, A., Enderlein, J.

Abstract:

Axonemes are the basic structure of motile cilia and flagella, and the investigation of how they function and move requires rapid three-dimensional imaging. We built a multi-plane phase-contrast microscope for imaging the three-dimensional motion of unlabeled flagella of the model organism Chlamydomonas reinhardtii with sub-m spatial and 4 ms temporal resolution. This allows us to observe not only bending but also the three-dimensional torsional dynamics of these small structures. We observe that flagella swim counter-clockwise close to a surface, with negatively-valued torsion at their basal and positively-valued torsion at their distal tips. To explain the torsional dynamics and signature, we suggest the existence of an intrinsic negative twist at the basal end that is untwisted by active positive-twist-inducing dynein motor proteins. Moreover, dyneins walking towards the basal induce an opposite twist at the distal tip. Bending of the whole axoneme structure then translates this twist into an observable torsion. This interconnection between chiral structure, twist, curvature, and torsion is fundamental for understanding flagellar mechanics.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.211904v1?rss=1

Authors: Goli Pozveh, S., Bae, A., Gholami, A.

Abstract:

Cilia-driven motility and fluid transport is ubiquitous in nature and essential for many biological processes, including swimming of eukaryotic unicellular organisms, mucus transport in airway apparatus or fluid flow in brain. The-biflagellated micro-swimmer Chlamydomonas reinhardtii is a model organism to study dynamics of flagellar synchronization. Hydrodynamic interactions, intracellular mechanical coupling or cell body rocking are believed to play crucial role in synchronization of flagellar beating in green algae. Here, we use freely swimming intact flagellar apparatus isolated from wall-less strain of Chlamydomonas to investigate wave dynamics. Our analysis in phase coordinates show that, when the frequency difference between the flagella is high, neither mechanical coupling via basal body nor hydrodynamics interactions are strong enough to synchronize two flagella, indicating that beating frequency is controlled internally by the cell. We also examined the validity of resistive force theory for a flagellar apparatus swimming freely in the vicinity of a substrate and found a quantitative agreement between experimental data and simulations with drag anisotropy of ratio 2. Finally, using a simplified wave form, we investigated the influence of phase and frequency differences, intrinsic curvature and wave amplitude on the swimming trajectory of flagellar apparatus. Our analysis shows that by controlling phase or frequency differences between two flagella, steering can occur.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.213124v1?rss=1

Authors: Saeed, A. F. U. H., Chan, C., Guo, H., Gong, B., Guo, P., Cheng, X., Ouyang, S.

Abstract:

Biological motors, ubiquitous in living systems, convert chemical energy into different kinds of mechanical motions critical to cellular functions. Most of these biomotors belong to a group of enzymes known as ATPases, which adopt a multi-subunit ring-shaped structure and hydrolyze adenosine triphosphate (ATP) to generate forces. The gene product 16 (gp16), an ATPase in bacteriophage {square}29, is among the most powerful biomotors known. It can overcome substantial resisting forces from entropic, electrostatic, and DNA bending sources to package double-stranded DNA (dsDNA) into a preformed protein shell (procapsid). Despite numerous studies of the {square}29 packaging mechanism, a structure of the full-length gp16 is still lacking, let alone that of the packaging motor complex that includes two additional molecular components: a connector gp10 protein and a prohead RNA (pRNA). Here we report the crystal structure of the C-terminal domain of gp16 (gp16-CTD). Structure-based alignment of gp16-CTD with related RNase H-like nuclease domains revealed a nucleic acid binding surface in gp16-CTD, whereas no nuclease activity has been detected for gp16. Subsequent molecular dynamics (MD) simulations showed that this nucleic acid binding surface is likely essential for pRNA binding. Furthermore, our simulations of a full-length gp16 structural model highlighted a dynamic interplay between the N-terminal domain (NTD) and CTD of gp16, which may play a role in driving DNA movement into the procapsid, providing structural support to the previously proposed inchworm model. Lastly, we assembled an atomic structural model of the complete {square}29 dsDNA packaging motor complex by integrating structural and experimental data from multiple sources. Collectively, our findings provided a refined inchworm-revolution model for dsDNA translocation in bacteriophage {square}29 and suggested how the individual domains of gp16 work together to power such translocation.

ABSTRACT (SHORT)Biological motors, ubiquitous in living systems, convert chemical energy into different kinds of mechanical motions critical to cellular functions. The gene product 16 (gp16) in bacteriophage {square}29 is among the most powerful biomotors known, which adopts a multi-subunit ring-shaped structure and hydrolyzes ATP to package double-stranded DNA (dsDNA) into a preformed procapsid. Here we report the crystal structure of the C-terminal domain of gp16 (gp16-CTD). Structure-based alignment and molecular dynamics (MD) simulations revealed an essential binding surface of gp16-CTD for prohead RNA (pRNA), a unique component of the motor complex. Furthermore, our simulations highlighted a dynamic interplay between the N-terminal domain (NTD) and CTD of gp16, which may play a role in driving DNA movement into the procapsid. Lastly, we assembled an atomic structural model of the complete {square}29 dsDNA packaging motor complex by integrating structural and experimental data from multiple sources. Collectively, our findings provided a refined inchworm-revolution model for dsDNA translocation in bacteriophage {square}29 and suggested how the individual domains of gp16 work together to power such translocation.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.21.214023v1?rss=1

Authors: Gramlich, M. W., Balseiro Gomez, S., Tabei, S. M. A., Parkes, M., Yogev, S.

Abstract:

Axonal motor driven cargo utilizes the microtubule cytoskeleton in order to direct cargo, such as presynaptic vesicle precursors, to where they are needed. This transport requires vesicles to travel up to microns in distance. It has recently been observed that finite microtubule lengths can act as roadblocks inhibiting vesicles and increasing the time required for transport. Vesicles reach the end of a microtubule and pause until they can navigate to a neighboring microtubule in order to continue transport. The mechanism by which axonal vesicles navigate the end of a microtubule in order to continue mobility is unknown. In this manuscript we model experimentally observed vesicle pausing at microtubule ends in C. elegans. We show that a single rate-constant model reproduces the time vesicles pause at MT-ends. This model is based on the time a vesicle must detach from its current microtubule and re-attach to a neighboring microtubule. We show that vesicle pause times are different for anterograde and retrograde motion, suggesting that vesicles utilize different proteins at plus and minus end sites. Last, we show that vesicles do not likely utilize a tug-of-war like mechanism and reverse direction in order to navigate microtubule ends.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.21.214072v1?rss=1

Authors: Tian, Y., Liang, R., Kumar, A., Szwedziak, P., Viles, J. H.

Abstract:

Amyloid-{beta} (A{beta}) monomers assemble into mature fibrils via a range of metastable oligomeric and protofibrillar intermediates. These A{beta} assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading to Alzheimers disease. However, molecular mechanisms of A{beta} cytotoxicity and how the different assembly forms interact with the membrane remain enigmatic. Here we use cryo-electron tomography (cryoET) to obtain three-dimensional nano-scale images of various A{beta} assembly types and their interaction with liposomes. A{beta} oligomers bind extensively to the lipid vesicles, inserting and carpeting the upper-leaflet of the bilayer. Furthermore, curvilinear protofibrils also insert into the bilayer, orthogonally to the membrane surface. A{beta} oligomers concentrate at the interface of vesicles and form a network of A{beta}-linked liposomes. While crucially, monomeric and fibrillar A{beta} have relatively little impact on the membrane. Changes to lipid membrane composition highlights a significant role for GM1-ganglioside in promoting A{beta}-membrane interactions. The different effects of A{beta} assembly forms observed align with the highlighted cytotoxicity reported for A{beta} oligomers. The wide-scale incorporation of A{beta} oligomers and curvilinear protofibrils into the lipid bilayer suggests a mechanism by which membrane integrity is lost.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.21.214098v1?rss=1

Authors: Hempel, T., Raich, L., Olsson, S., Azouz, N. P., Klingler, A. M., Rothenberg, M. E., Noe, F.

Abstract:

The entry of the coronavirus SARS-CoV-2 into human cells can be inhibited by the approved drugs camostat and nafamostat. Here we elucidate the molecular mechanism of these drugs by combining experiments and simulations. In vitro assays confirm the hypothesis that both drugs act by inhibiting the human protein TMPRSS2. As no experimental structure is available, we provide a model of the TMPRSS2 equilibrium structure and its fluctuations by relaxing an initial homology structure with extensive 280 microseconds of all-atom molecular dynamics (MD) and Markov modeling. We describe the binding mode of both drugs with TMPRSS2 in a Michaelis complex (MC) state preceding the formation of a long-lived covalent inhibitory state. We find that nafamostat to has a higher MC population, which in turn leads to the more frequent formation of the covalent complex and thus higher inhibition efficacy, as confirmed in vitro and consistent with previous virus cell entry assays. Our TMPRSS2-drug structures are made public to guide the design of more potent and specific inhibitors.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.211169v1?rss=1

Authors: Chen, M., Chen, X., Jin, S., Lu, W., Lin, X., Wolynes, P. G.

Abstract:

1Recent advances in machine learning, bioinformatics and the understanding of the folding problem have enabled efficient predictions of protein structures with moderate accuracy, even for targets when there is little information from templates. All-atom molecular dynamics simulations provide a route to refine such predicted structures, but unguided atomistic simulations, even when lengthy in time, often fail to eliminate incorrect structural features that would allow the structure to become more energetically favorable owing to the necessity of making large scale motions and overcoming energy barriers for side chain repacking. In this study, we show that localizing packing frustration at atomic resolution by examining the statistics of the energetic changes that occur when the local environment of a site is changed allows one to identify the most likely locations of incorrect contacts. The global statistics of atomic resolution frustration in structures that have been predicted using various algorithms provide strong indicators of structural quality when tested over a database of 20 targets from previous CASP experiments. Residues that are more correctly located turn out to be more minimally frustrated than more poorly positioned sites. These observations provide a diagnosis of both global and local quality of predicted structures, and thus can be used as guidance in all-atom refinement simulations of the 20 targets. Refinement simulations guided by atomic packing frustration turn out to be quite efficient and significantly improve the quality of the structures.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.212068v1?rss=1

Authors: Polydorides, S., Archontis, G.

Abstract:

The coronavirus SARS-CoV-2, that is responsible for the COVID-19 pandemic, and the closely related SARS-CoV coronavirus enter cells by binding at the human angiotensin converting enzyme 2 (hACE2). The stronger hACE2 affinity of SARS-CoV-2 has been connected with its higher infectivity. In this work, we study hACE2 complexes with the receptor binding domains (RBDs) of the human SARS-CoV-2 and human SARS-CoV viruses, using all-atom molecular dynamics (MD) simulations and Computational Protein Design (CPD) with a physics-based energy function. The MD simulations identify charge-modifying substitutions between the CoV-2 and CoV RBDs, which either increase or decrease the hACE2 affinity of the SARS-CoV-2 RBD. The combined effect of these mutations is small, and the relative affinity is mainly determined by substitutions at residues in contact with hACE2. Many of these findings are in line and interpret recent experiments. Our CPD calculations redesign positions 455, 493, 494 and 501 of the SARS-CoV-2 RBM, which contact hACE2 in the complex and are important for ACE2 recognition. Sampling is enhanced by an adaptive importance sampling Monte Carlo method. Sequences with increased affinity replace CoV-2 glutamine by a negative residue at position 493, and serine by nonpolar, aromatic or a threonine at position 494. Substitutions at positions positions 455 and 501 have a smaller effect on affinity. Substitutions suggested by our design are seen in viral sequences encountered in other species, including bat and pangolin. Our results might be used to identify potential virus strains with higher human infectivity and assist in the design of peptide-based or peptidomimetic compounds with the potential to inhibit SARS-CoV-2 binding at hACE2.

SIGNIFICANCEThe coronavirus SARS-CoV-2 is responsible for the current COVID-19 pandemic. SARS-CoV-2 and the earlier, closely related SARS-CoV virus bind at the human angiotensin converting enzyme 2 (hACE2) receptor at the cell surface. The higher human infectivity of SARS-CoV-2 may be linked to its stronger affinity for hACE2. Here, we study by computational methods complexes of hACE2 with the receptor binding domains (RBDs) of viruses SARS-CoV-2 and SARS-CoV. We identify residues affecting the affinities of the two domains for hACE2. We also propose mutations at key SARS-CoV-2 positions, which might enhance hACE2 affinity. Such mutations may appear in viral strains with increased human infectivity and might assist the design of peptide-based compounds that inhibit infection of human cells by SARS-CoV-2.

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