Molecular Dynamics of Major Allergens from <i>Alternaria</i>, Birch Pollen and Peach

Garrido‐Arandia, María; Gómez‐Casado, Cristina; Díaz‐Perales, Araceli; Pacios, Luis F.

doi:10.1002/minf.201400057

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…As described above, Bet v 1 is among the most extensively studied allergen proteins in experiment, computational models and clinical studies (Spangfort et al, 2003;Bollen et al, 2010;Berkner et al, 2014;Garrido-Arandia et al, 2014;Grutsch et al, 2014;Kitzmuller et al, 2015;Kamenik et al, 2016;Moingeon et al, 2016;Biedermann et al, 2019). With an estimated 100 million of individuals suffering from birch pollen allergy, it is also one of the clinically most relevant allergens (Hartl et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Kamenik

Hofer

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et al. 2020

Front. Mol. Biosci.

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Proteolytic susceptibility during endolysosomal degradation is decisive for allergic sensitization. In the major birch pollen allergen Bet v 1 most protease cleavage sites are located within its secondary structure elements, which are inherently inaccessible to proteases. The allergen thus must unfold locally, exposing the cleavage sites to become susceptible to proteolysis. Hence, allergen cleavage rates are presumed to be linked to their fold stability, i.e., unfolding probability. Yet, these locally unfolded structures have neither been captured in experiment nor simulation due to limitations in resolution and sampling time, respectively. Here, we perform classic and enhanced molecular dynamics (MD) simulations to quantify fold dynamics on extended timescales of Bet v 1a and two variants with higher and lower cleavage rates. Already at the nanosecond-timescale we observe a significantly higher flexibility for the destabilized variant compared to Bet v 1a and the proteolytically stabilized mutant. Estimating the thermodynamics and kinetics of local unfolding around an initial cleavage site, we find that the Bet v 1 variant with the highest cleavage rate also shows the highest probability for local unfolding. For the stabilized mutant on the other hand we only find minimal unfolding probability. These results strengthen the link between the conformational dynamics of allergen proteins and their stability during endolysosomal degradation. The presented approach further allows atomistic insights in the conformational ensemble of allergen proteins and provides probability estimates below experimental detection limits.

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Section: Introductionmentioning

confidence: 99%

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Kamenik

Hofer

Handle

et al. 2020

Front. Mol. Biosci.

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“…is unknown, as is the function of the majority of these fungal allergenic products. Recent works suggest that Alt a 1 plays an important role in phytopathogenesis (Gomez-Casado et al 2014;Garrido-Arandia et al 2014) Characterization of Alternaria species has historically been based on morphological features of the conidia and sporulation apparatus. Simmons (2007) published an identification manual, intended to cover the entire genus with detailed descriptions, drawings, culture, and isolation media.…”

Section: Introductionmentioning

confidence: 99%

Molecular diversity and allergenic profiles of Alternaria spp. from desert environments in Arizona

et al. 2018

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This study examined the genetic diversity of small-spored Alternaria species in the southwest desert of the USA by sampling 552 isolates from different habitats (soil and plant debris) in different locations (urban and an undisturbed desert). To estimate the genetic diversity, Amplified Fragment Length Polymorphism (AFLP) fingerprinting analysis was performed for all isolates. Strains representative of the sampled genotypic diversity (n = 125) were further characterized according their sporulation pattern and the capability to produce allergens. Morphological characterization assigned the majority of the strains to the Alternaria alternata and Alternaria tenuissima morpho-groups with only two isolates assigned to the Alternaria arborescens morpho-group. AFLP fingerprinting differentiated the A. arborescens morpho-groups, but could not distinguish between the A. alternata and A. tenuissima morpho-groups. Western blot analysis showed that a large number of allergenic proteins were produced by strains. These proteins were not specific for any morpho-group nor source of isolation. A hierarchical analysis of molecular variance was performed on the AFLP data to quantify molecular variation and partition this variation among sampled locations and habitat. No statistically significant differentiation among locations and habitat was detected indicating a lack of population structure across environments.

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“…The development of a practical method for aggregate structure prediction based on the geometry of a particular antigen conformation could be useful not only for understanding aggregation, but also for possible manipulation of the antigen geometry to obtain a desired aggregate structure. Various properties of allergens and protein complexes, such as structural stability, flexibility, and dimerization, have been studied using molecular dynamics-based methods [ 10 , 11 ]; however, such methods would not be useful to study antibody aggregation due to the long timescales involved (on the order of seconds) and the large size and quantity of the aggregates that may form.…”

Section: Introductionmentioning

confidence: 99%

Extending rule-based methods to model molecular geometry and 3D model resolution

et al. 2016

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BackgroundComputational modeling is an important tool for the study of complex biochemical processes associated with cell signaling networks. However, it is challenging to simulate processes that involve hundreds of large molecules due to the high computational cost of such simulations. Rule-based modeling is a method that can be used to simulate these processes with reasonably low computational cost, but traditional rule-based modeling approaches do not include details of molecular geometry. The incorporation of geometry into biochemical models can more accurately capture details of these processes, and may lead to insights into how geometry affects the products that form. Furthermore, geometric rule-based modeling can be used to complement other computational methods that explicitly represent molecular geometry in order to quantify binding site accessibility and steric effects.ResultsWe propose a novel implementation of rule-based modeling that encodes details of molecular geometry into the rules and binding rates. We demonstrate how rules are constructed according to the molecular curvature. We then perform a study of antigen-antibody aggregation using our proposed method. We simulate the binding of antibody complexes to binding regions of the shrimp allergen Pen a 1 using a previously developed 3D rigid-body Monte Carlo simulation, and we analyze the aggregate sizes. Then, using our novel approach, we optimize a rule-based model according to the geometry of the Pen a 1 molecule and the data from the Monte Carlo simulation. We use the distances between the binding regions of Pen a 1 to optimize the rules and binding rates. We perform this procedure for multiple conformations of Pen a 1 and analyze the impact of conformation and resolution on the optimal rule-based model.ConclusionsWe find that the optimized rule-based models provide information about the average steric hindrance between binding regions and the probability that antibodies will bind to these regions. These optimized models quantify the variation in aggregate size that results from differences in molecular geometry and from model resolution.

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Molecular Dynamics of Major Allergens from Alternaria, Birch Pollen and Peach

Cited by 11 publications

References 37 publications

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Molecular diversity and allergenic profiles of Alternaria spp. from desert environments in Arizona

Extending rule-based methods to model molecular geometry and 3D model resolution

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