scholarly journals Multiscale Models for Fibril Formation: Rare Events Methods, Microkinetic Models, and Population Balances

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 570
Author(s):  
Armin Shayesteh Zadeh ◽  
Baron Peters
Keyword(s):  
Rate Constants ◽  
Amyloid Fibrils ◽  
Rare Events ◽  
Fibril Formation ◽  
Potential Of Mean Force ◽  
Maximum Likelihood Estimates ◽  
Balance Model ◽  
Growth Data ◽  
Microkinetic Model ◽  
Population Balances

Amyloid fibrils are thought to grow by a two-step dock-lock mechanism. However, previous simulations of fibril formation (i) overlook the bi-molecular nature of the docking step and obtain rates with first-order units, or (ii) superimpose the docked and locked states when computing the potential of mean force for association and thereby muddle the docking and locking steps. Here, we developed a simple microkinetic model with separate locking and docking steps and with the appropriate concentration dependences for each step. We constructed a simple model comprised of chiral dumbbells that retains qualitative aspects of fibril formation. We used rare events methods to predict separate docking and locking rate constants for the model. The rate constants were embedded in the microkinetic model, with the microkinetic model embedded in a population balance model for “bottom-up” multiscale fibril growth rate predictions. These were compared to “top-down” results using simulation data with the same model and multiscale framework to obtain maximum likelihood estimates of the separate lock and dock rate constants. We used the same procedures to extract separate docking and locking rate constants from experimental fibril growth data. Our multiscale strategy, embedding rate theories, and kinetic models in conservation laws should help to extract docking and locking rate constants from experimental data or long molecular simulations with correct units and without compromising the molecular description.

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

scholarly journals ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

2015 ◽  
Vol 59 (9) ◽  
pp. 5123-5134 ◽  
Author(s):  
Tianrong Xun ◽  
Wenjuan Li ◽  
Jinquan Chen ◽  
Fei Yu ◽  
Wei Xu ◽  
...  
Keyword(s):  
Viral Infection ◽  
Amyloid Fibrils ◽  
Synergistic Effects ◽  
Sexual Transmission ◽  
Prostatic Acid Phosphatase ◽  
Fibril Formation ◽  
Antiretroviral Drugs ◽  
Target Cells ◽  
Additional Function ◽  
Hiv 1

ABSTRACTSemen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248–286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.

scholarly journals Data Mining Crystallization Kinetics

2020 ◽  
Author(s):  
Cameron Brown ◽  
Diego Maldonado ◽  
Antony Vassileiou ◽  
Blair Johnston ◽  
Alastair Florence
Keyword(s):  
Random Forest ◽  
Kinetic Parameters ◽  
Crystallization Kinetics ◽  
Balance Model ◽  
Forest Models ◽  
Vast Literature ◽  
Random Forest Models ◽  
Kinetic Expression ◽  
Population Balances ◽  
Different Sources

<p>Population balance model is a valuable modelling tool which facilitates the optimization and understanding of crystallization processes. However, in order to use this tool, it is necessary to have previous knowledge of the crystallization kinetics, specifically crystal growth and nucleation. The majority of approaches to achieve proper estimations of kinetic parameters required experimental data. Across time, a vast literature about the estimation of kinetic parameters and population balances have been published. Considering the availability of data, this work built a database with information on solute, solvent, kinetic expression, parameters, crystallization method and seeding. Correlations were assessed and clusters structures identified by hierarchical clustering analysis. The final database contains 336 data of kinetic parameters from 185 different sources. The data were analysed using kinetic parameters of the most common expressions. Subsequently, clusters were identified for each kinetic model. With these clusters, classification random forest models were made using solute descriptors, seeding, solvent, and crystallization methods as classifiers. Random forest models had an overall classification accuracy higher than 70% whereby they were useful to provide rough estimates of kinetic parameters, although these methods have some limitations.</p>

scholarly journals The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

2021 ◽  
Vol 118 (3) ◽  
pp. e2014442118
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo D. Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

scholarly journals Adsorption of unfolded Cu/Zn superoxide dismutase onto hydrophobic surfaces catalyzes its formation of amyloid fibrils

2019 ◽  
Vol 32 (2) ◽  
pp. 77-85
Author(s):  
Mohammad Ashhar I Khan ◽  
Ulrich Weininger ◽  
Sven Kjellström ◽  
Shashank Deep ◽  
Mikael Akke
Keyword(s):  
Superoxide Dismutase ◽  
Surface Area ◽  
Amyloid Fibrils ◽  
Hydrophobic Surface ◽  
Fibril Formation ◽  
Hydrophobic Surfaces ◽  
Molecular Features ◽  
Denaturant Concentration

Abstract Intracellular aggregates of superoxide dismutase 1 (SOD1) are associated with amyotrophic lateral sclerosis. In vivo, aggregation occurs in a complex and dense molecular environment with chemically heterogeneous surfaces. To investigate how SOD1 fibril formation is affected by surfaces, we used an in vitro model system enabling us to vary the molecular features of both SOD1 and the surfaces, as well as the surface area. We compared fibril formation in hydrophilic and hydrophobic sample wells, as a function of denaturant concentration and extraneous hydrophobic surface area. In the presence of hydrophobic surfaces, SOD1 unfolding promotes fibril nucleation. By contrast, in the presence of hydrophilic surfaces, increasing denaturant concentration retards the onset of fibril formation. We conclude that the mechanism of fibril formation depends on the surrounding surfaces and that the nucleating species might correspond to different conformational states of SOD1 depending on the nature of these surfaces.

Prion Protein Aggregation Induced by Copper(II) and Heparan Sulfate. Pressure-dependent Switch of Reaction Pathways

2008 ◽  
Vol 63 (6) ◽  
pp. 747-755 ◽  
Author(s):  
Driss El Moustaine ◽  
Joan Torrent ◽  
Reinhard Lange
Keyword(s):  
Heparan Sulfate ◽  
Prion Protein ◽  
Conformational Changes ◽  
Atmospheric Pressure ◽  
Amyloid Fibrils ◽  
Copper Ions ◽  
Fibril Formation ◽  
Cellular Prion Protein ◽  
Reaction Pathways ◽  
Structural Alterations

Copper ions (Cu2+) and heparan sulfate (HS) are suspected to act as regulatory agents in the conversion of cellular prion protein (PrPC) to its infectious isoform. However, the mechanism of this reaction is still largely unknown. Our previous report suggested multidimensional pathways for structural alterations of PrP, which may be modulated by high pressure (HP). Here we use HP to investigate the effects of Cu2+ and HS binding on PrP conformational changes and assembly. In the presence of Cu2+, amyloid fibrils are formed only under HP. In contrast, in the presence of HS, fibrils are formed at atmospheric pressure, but not under HP. Both compounds appear to compete for the same binding site, since HS-supported fibril formation is quenched by Cu2+. Inversely, Cu2+- mediated fibril formation under HP is inhibited by HS.

scholarly journals Data Mining Crystallization Kinetics

2020 ◽  
Author(s):  
Cameron Brown ◽  
Diego Maldonado ◽  
Antony Vassileiou ◽  
Blair Johnston ◽  
Alastair Florence
Keyword(s):  
Random Forest ◽  
Kinetic Parameters ◽  
Crystallization Kinetics ◽  
Balance Model ◽  
Forest Models ◽  
Vast Literature ◽  
Random Forest Models ◽  
Kinetic Expression ◽  
Population Balances ◽  
Different Sources

<p>Population balance model is a valuable modelling tool which facilitates the optimization and understanding of crystallization processes. However, in order to use this tool, it is necessary to have previous knowledge of the crystallization kinetics, specifically crystal growth and nucleation. The majority of approaches to achieve proper estimations of kinetic parameters required experimental data. Across time, a vast literature about the estimation of kinetic parameters and population balances have been published. Considering the availability of data, this work built a database with information on solute, solvent, kinetic expression, parameters, crystallization method and seeding. Correlations were assessed and clusters structures identified by hierarchical clustering analysis. The final database contains 336 data of kinetic parameters from 185 different sources. The data were analysed using kinetic parameters of the most common expressions. Subsequently, clusters were identified for each kinetic model. With these clusters, classification random forest models were made using solute descriptors, seeding, solvent, and crystallization methods as classifiers. Random forest models had an overall classification accuracy higher than 70% whereby they were useful to provide rough estimates of kinetic parameters, although these methods have some limitations.</p>

scholarly journals Study of Nanofibrils Formation of Fibroin Protein in Specific Thermal and Acidity Conditions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M Ahrami
Keyword(s):  
Electron Microscopy ◽  
Amyloid Fibrils ◽  
Thermal Conditions ◽  
Fibril Formation ◽  
Fibrillar Structure ◽  
Transmission Electron ◽  
Vis Spectroscopy ◽  
Wide Range ◽  
Model Protein ◽  
Bombyx Mori Silk

Abstract Background: Amyloid fibrils are insoluble arranged aggregates of proteins that are fibrillar in structure and related to many diseases (at least 20 types of illnesses) and also create many pathologic conditions. Therefore understanding the circumstance of fibril formation is very important. Objectives: This study aims to work on fibrillar structure formation of fibroin (as a model protein). Material and Methods: In this experimental study, fibroin was extracted from bombyx mori silk cocoon, and the concentration was obtained by Bradford method. The protein was incubated in a wide range of times (0 min to 7 days) in specific acidity and thermal conditions (pH=1.6, T=70 °C). The assays of UV-vis spectroscopy with congo red, field emission scanning electron microscopy, transmission electron microscopy, atomic force microscopy and circular dichroism spectroscopy were employed to monitor the fibrillation process. Results: Fibroin assemblies were formed upon the process of aggregation and fibril formation with a variety of morphology ranging from nanoparticles to elongated fibrils. Conclusion: The results showed progressive pathway of fibril formation.

scholarly journals Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules

2020 ◽  
Author(s):  
Emma Cawood ◽  
Nicolas Guthertz ◽  
Jessica Ebo ◽  
Theodoros Karamanos ◽  
Sheena E. Radford FRS ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Structural Characterization ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Fibril Formation ◽  
X Ray Crystallography ◽  
Starting Point ◽  
Amyloid Assembly

<p></p><p>Protein-protein interactions (PPIs) are involved in many of life’s essential biological functions yet are also an underlying cause of several human diseases, including amyloidosis. The modulation of PPIs presents opportunities to gain mechanistic insights into amyloid assembly, particularly through the use of methods which can trap specific intermediates for detailed study. Such information can also provide a starting point for drug discovery. Here, we demonstrate that covalently tethered small molecule fragments can be used to stabilize specific oligomers during amyloid fibril formation, facilitating the structural characterization of these assembly intermediates. We exemplify the power of covalent tethering using the naturally occurring truncated variant (ΔN6) of the human protein β2-microglobulin (β2m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped oligomeric species using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of “post-translational chemical modification" as a tool to study biological molecular mechanisms. </p><br><p></p>

scholarly journals Modification of insulin amyloid aggregation by Zr phthalocyanines functionalized with dehydroacetic acid derivatives

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243904
Author(s):  
Svitlana Chernii ◽  
Yuriy Gerasymchuk ◽  
Mykhaylo Losytskyy ◽  
Damian Szymański ◽  
Iryna Tretyakova ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Cluster Formation ◽  
Aromatic Amino Acids ◽  
Functional Materials ◽  
Fibril Formation ◽  
Dehydroacetic Acid ◽  
Protein Fibrils ◽  
Conformational Disorders ◽  
Free Insulin ◽  
Out Of Plane

Amyloid fibrils are widely studied both as target in conformational disorders and as basis for the development of protein-based functional materials. The three Zr phthalocyanines bearing dehydroacetic acid residue (PcZr(L1)2) and its condensed derivatives (PcZr(L2)2 and PcZr(L3)2) as out-of-plane ligands were synthesized and their influence on insulin fibril formation was studied by amyloid-sensitive fluorescent dye based assay, scanning electron microscopy, fluorescent and absorption spectroscopies. The presence of Zr phthalocyanines was shown to modify the fibril formation. The morphology of fibrils formed in the presence of the Zr phthalocyanines differs from that of free insulin and depends on the structure of out-of-plane ligands. It is shown that free insulin mostly forms fibril clusters with the length of about 0.3–2.1 μm. The presence of Zr phthalocyanines leads to the formation of individual 0.4–2.8 μm-long fibrils with a reduced tendency to lateral aggregation and cluster formation (PcZr(L1)2), shorter 0.2–1.5 μm-long fibrils with the tendency to lateral aggregation without clusters (PcZr(L2)2), and fibril-like 0.2–1.0 μm-long structures (PcZr(L3)2). The strongest influence on fibrils morphology made by PcZr(L3)2 could be explained by the additional stacking of phenyl moiety of the ligand with aromatic amino acids in protein. The evidences of binding of studied Zr phthalocyanines to mature fibrils were shown by absorption spectroscopy (for PcZr(L1)2 and PcZr(L2)2) and fluorescent spectroscopy (for PcZr(L3)2). These complexes could be potentially used as external tools allowing the development of functional materials on protein fibrils basis.

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