scholarly journals Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure

2021 ◽  
Vol 17 (12) ◽  
pp. e1009664
Author(s):  
Assaf Amitai
Keyword(s):  
Md Simulations ◽  
Main Axis ◽  
Coarse Grained ◽  
Surface Geometry ◽  
Antibody Targeting ◽  
In Silico Models ◽  
Key Residues ◽  
Viral Surface ◽  
Influenza H1n1

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.

scholarly journals Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure

2020 ◽  
Author(s):  
Assaf Amitai
Keyword(s):  
Antibody Response ◽  
Computational Models ◽  
Seasonal Influenza ◽  
H1n1 Pandemic ◽  
Surface Geometry ◽  
Antigenic Sites ◽  
2009 H1n1 ◽  
Viral Surface ◽  
Over Time ◽  
Influenza H1n1

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.

scholarly journals Formation of aggregates, icosahedral structures and percolation clusters of fullerenes in lipids bilayers: The key role of lipid saturation

2020 ◽  
Author(s):  
Nililla Nisoh ◽  
Viwan Jarerattanachat ◽  
Mikko Karttunen ◽  
Jirasak Wong-ekkabut
Keyword(s):  
Lipid Bilayers ◽  
Carbon Nanoparticles ◽  
Md Simulations ◽  
Coarse Grained ◽  
Percolation Clusters ◽  
High Fullerene ◽  
Key Factor ◽  
Chain Lengths ◽  
Lateral Area

AbstractCarbon nanoparticles (CNPs) are attractive materials for a great number of applications but there are serious concerns regarding their influence on health and environment. Here, our focus is on the behavior of fullerenes in lipid bilayers with varying lipid saturations, chain lengths and fullerene concentrations using coarse-grained molecular dynamics (CG-MD) simulations. Our findings show that the lipid saturation level is a key factor in determining how fullerenes behave and where the fullerenes are located inside a lipid bilayer. In saturated and monounsaturated bilayers fullerenes aggregated and formed clusters with some of them showing icosahedral structures. In polyunsaturated lipid bilayers, no such structures were observed: In polyunsaturated lipid bilayers at high fullerene concentrations, connected percolation-like networks of fullerenes spanning the whole lateral area emerged at the bilayer center. In other systems only separate isolated aggregates were observed. The effects of fullerenes on lipid bilayers depend strongly on fullerene aggregation. When fullerenes aggregate, their interactions with the lipid tails change.

Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires

2019 ◽  
Author(s):  
Bella Grigorenko ◽  
Igor Polyakov ◽  
Alexander Nemukhin
Keyword(s):  
Adenylyl Cyclase ◽  
Bond Cleavage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Md Simulations ◽  
Coordination Shell ◽  
Energy Profile ◽  
One Step ◽  
Type V

<p>We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of Mg<sub>A</sub><sup>2+ </sup>are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of Mg<sub>A</sub><sup>2+ </sup>does not include the O<sub>δ1</sub> atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O<sup>3'</sup>H<sup>3' </sup>group in ATP to Asp440 via a shuttling water molecule and P<sup>A</sup>-O<sup>3A</sup> bond cleavage and O<sup>3'</sup>-P<sup>A</sup> bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, Mg<sub>A</sub><sup>2+</sup> is bound to the O<sub>δ1</sub>(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O<sup>3'</sup>H<sup>3' </sup>group via shuttling water molecules. </p>

Biochemical study of fibrinolytic protease from Euphausia superba possessing multifunctional serine protease activity

2020 ◽  
Vol 27 ◽  
Author(s):  
Guo-Ying Qian ◽  
Gyutae Lim ◽  
Shang-Jun Yin ◽  
Jun-Mo Yang ◽  
Jinhyuk Lee ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Fluorescence Spectra ◽  
Biochemical Study ◽  
Euphausia Superba ◽  
Md Simulations ◽  
Time Interval ◽  
Serine Residue ◽  
Catalytic Function ◽  
Serine Protease Activity ◽  
Key Residues

Background: Background: Fibrinolytic protease from Euphausia superba (EFP) was isolated. Objective: Biochemical distinctions, regulation of the catalytic function, and the key residues of EFP were investigated. Methods: The serial inhibition kinetic evaluations coupled with measurements of fluorescence spectra in the presence of 4- (2-aminoethyl) benzene sulfonyl fluoride hydrochloride (AEBSF) was conducted. The computational molecular dynamics (MD) simulations were also applied for a comparative study. Results: The enzyme behaved as a monomeric protein with a molecular mass of about 28.6 kD with Km BApNA = 0.629 ± 0.02 mM and kcat/Km BApNA = 7.08 s-1 /mM. The real-time interval measurements revealed that the inactivation was a first-order reaction, with the kinetic processes shifting from a monophase to a biphase. Measurements of fluorescence spectra showed that serine residue modification by AEBSF directly caused conspicuous changes of the tertiary structures and exposed hydrophobic surfaces. Some osmolytes were applied to find protective roles. These results confirmed that the active region of EFP is more flexible than the overall enzyme molecule and serine, as the key residue, is associated with the regional unfolding of EFP in addition to its catalytic role. The MD simulations were supportive to the kinetics data. Conclusion: Our study indicated that EFP has an essential serine residue for its catalyst function and associated folding behaviors. Also, the functional role of osmolytes such as proline and glycine that may play a role in defense mechanisms from environmental adaptation in a krill’s body was suggested.

scholarly journals Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Baolei Yuan ◽  
Jordy Homing Lam ◽  
Jun Zhou ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Md Simulation ◽  
Potential Role ◽  
Md Simulations ◽  
Full Length ◽  
Inflammasome Activation ◽  
Simulation Studies ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

scholarly journals Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Dang ◽  
Yifan Li ◽  
Jianxing Song
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Atp Binding ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Nucleic Acid Binding ◽  
General Role ◽  
Nmr Characterization ◽  
Lateral Sclerosis

AbstractTDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

scholarly journals Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3293
Author(s):  
Mateusz Zalewski ◽  
Sebastian Kmiecik ◽  
Michał Koliński
Keyword(s):  
Molecular Dynamics ◽  
Geometry Optimization ◽  
Computational Prediction ◽  
Md Simulations ◽  
Coarse Grained ◽  
Ligand Interaction ◽  
Vast Number ◽  
Docking Simulations ◽  
Peptide Models ◽  
Peptide Complexes

One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.

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