Effect of attaching hydrophilic oligopeptides to the C-terminus of organic solvent-tolerant metal-free bromoperoxidase BPO-A1 from Streptomyces aureofaciens on organic solvent-stability.

Metal-free bromoperoxidase BPO-A1 from Streptomyces aureofacience was selected among several similar enzymes exhibiting brominating activity as the most stable haloperoxidase against 70%(v/v) methanol. A comparison of the BPO-A1 and octahistidine-tagged BPO-A1 at the C-terminus (BPO-A1-His8) revealed that the His-tag enhanced the organic solvent-stability of BPO-A1 with pH- and heat-stabilities. Additionally, the contribution of the hydrophilicity at the C-terminal of BPO-A1 to the organic solvent-stability was confirmed employing several mutants bearing hydrophilic oligopeptides. Fortunately, two excellent mutants, BPO-A1-Lys8 and BPO-A1-Arg8, with high stabilities against various water-miscible organic solvents were obtained. In conclusion, the enhancing effect of the hydrophilic oligopeptides on the organic solvent-stability was associated with a decrease in the hydrophobic surface area near the C-terminus.

Highly Similar Tetramerization Domains from the p53 Protein of Different Mammalian Species Possess Varying Biophysical, Functional and Structural Properties.

The p53 protein is a transcriptional regulatory factor and many of its functions require that it forms a tetrameric structure. Although the tetramerization domain of mammalian p53 proteins (p53TD) share significant sequence similarities, it was recently shown that the tree shrew p53TD is considerably more thermostable than the human p53TD. To determine whether other mammalian species display differences in this domain, we used biophysical, functional, and structural studies to compare the properties of the p53TDs from six mammalian model organisms (human, tree shrew, guinea pig, Chinese hamster, sheep, and opossum). The results indicate that the p53TD from the opossum and tree shrew are significantly more stable than the human p53TD, and there is a correlation between the thermostability of the p53TDs and their ability to activate transcription. Structural analysis of the tree shrew and opossum p53TDs indicated that amino acid substitutions within two distinct regions of their p53TDs can dramatically alter hydrophobic packing of the tetramer, and in particular substitutions at positions corresponding to F341 and Q354 of the human p53TD. Together, the results suggest that subtle changes in the sequence of the p53TD can dramatically alter the stability, and potentially lead to important changes in the functional activity, of the p53 protein.

Can the jigsaw puzzle model of protein folding re-assemble a hydrophobic core?

According to the "jigsaw puzzle" model of protein folding, the isomorphism between sequence and structure is substantially determined by the specific geometry of side-chain interactions, within the protein interior. In this work, we have attempted to predict the hydrophobic core of cyclophilin (LdCyp) from Leishmania donovani, utilizing a surface complementarity function, which selects for high goodness of fit between hydrophobic side-chain surfaces, rather in the manner of assembling a three-dimensional jigsaw puzzle. The computational core prediction method implemented here has been tried on two distinct scenarios, on the LdCyp polypeptide chain with native non-core residues and all core residues initially set to alanine, on a poly-glycine polypeptide chain. Molecular dynamics simulations appeared to indicate partial destabilization of the two designed sequences. However, experimental characterization of the designed sequences by circular dichroism (CD) spectroscopy and denaturant (GdmCl) induced unfolding, demonstrated disordered proteins. Stepwise reconstruction of the designed cores by cumulative sequential mutations identified the specific mutation (M122L) as primarily responsible for fold collapse and all design objectives were achieved upon rectifying this mutation. In summary, the study demonstrates regions of the core to contain highly specific (jigsaw puzzle-like) interactions sensitive to any perturbations and a predictive algorithm to identify such regions. A mutation within the core has been identified which exercises an inordinate influence on the global fold, reminiscent of metamorphic proteins. In addition, the computational procedure could predict substantial regions of the core (given main-chain coordinates) without any reference to non-core residues.

N-Terminus-Mediated Solution Structure of Dimerization Domain of PRC1.

Microtubule-associated proteins (MAPs) are essential for the accurate division of a cell into two daughter cells. These proteins target specific microtubules to be incorporated into the spindle midzone, which comprises a special array of microtubules that initiate cytokinesis during anaphase. A representative member of the MAPs is Protein Regulator of Cytokinesis 1 (PRC1), which self-multimerizes to cross-link microtubules, the malfunction of which might result in cancerous cells. The importance of PRC1 multimerization makes it a popular target for structural studies. The available crystal structure of PRC1 has low resolution (>3 Å) and accuracy, limiting a better understanding of the structure-related functions of PRC1. Therefore, we used NMR spectroscopy to better determine the structure of the dimerization domain of PRC1. The NMR structure shows that the PRC1 N terminus is crucial to the overall structure integrity, but the crystal structure bespeaks otherwise. We systematically addressed the role of the N terminus by generating a series of mutants in which N-terminal residues methionine (Met1) and arginine (Arg2) were either deleted, extended or substituted with other rationally selected amino acids. Each mutant was subsequently analyzed by NMR spectroscopy or fluorescence thermal shift assays for its structural or thermal stability; we found that N-terminal perturbations indeed affected the overall protein structure and that the solution structure better reflects the conformation of PRC1 under solution conditions. These results reveal that the structure of PRC1 is governed by its N terminus through hydrophobic interactions with other core residues, such hitherto unidentified N-terminal conformations might shed light on the structure−function relationships of PRC1 or other proteins. Therefore, our study is of major importance in terms of identifying a novel structural feature and can further the progress of protein folding and protein engineering.

Divergence Entropy-Based Evaluation of Hydrophobic Core in Aggressive and Resistant Forms of Transthyretin.

The two forms of transthyretin differing slightly in the tertiary structure, despite the presence of five mutations, show radically different properties in terms of susceptibility to the amyloid transformation process. These two forms of transthyretin are the object of analysis. The search for the sources of these differences was carried out by means of a comparative analysis of the structure of these molecules in their native and early intermediate stage forms in the folding process. The criterion for assessing the degree of similarity and differences is the status of the hydrophobic core. The comparison of the level of arrangement of the hydrophobic core and its initial stages is possible thanks to the application of divergence entropy for the early intermediate stage and for the final forms. It was shown that the minimal differences observed in the structure of the hydrophobic core of the forms available in PDB, turned out to be significantly different in the early stage (ES) structure in folding process. The determined values of divergence entropy for both ES forms indicate the presence of the seed of hydrophobic core only in the form resistant to amyloid transformation. In the form of aggressively undergoing amyloid transformation, the structure lacking such a seed is revealed, being a stretched one with a high content of ß-type structure. In the discussed case, the active presence of water in the structural transformation of proteins expressed in the fuzzy oil drop model (FOD) is of decisive importance for the generation of the final protein structure. It has been shown that the resistant form tends to generate a centric hydrophobic core with the possibility of creating a globular structure, i.e., a spherical micelle-like form. The aggressively transforming form reveals in the structure of its early intermediate, a tendency to form the ribbon-like micelle as observed in amyloid.

Finding the generalized molecular principles of protein thermal stability.

Are there any generalized molecular principles of thermal adaptation? Here, integrating the concepts of structural bioinformatics, sequence analysis, and classical knot theory, we develop a robust computational framework that seeks for mechanisms of thermal adaptation by comparing orthologous mesophilic-thermophilic and mesophilic-hyperthermophilic proteins of remarkable structural and topological similarities, and still leads us to context-independent results. A comprehensive analysis of 4741 high-resolution, non-redundant X-ray crystallographic structures collected from 11 hyperthermophilic, 32 thermophilic and 53 mesophilic prokaryotes unravels at least five "nearly universal" signatures of thermal adaptation, irrespective of the enormous sequence, structure, and functional diversity of the proteins compared. A careful investigation further extracts a set of amino acid changes that can potentially enhance protein thermal stability, and remarkably, these mutations are overrepresented in protein crystallization experiments, in disorder-to-order transitions and in engineered thermostable variants of existing mesophilic proteins. These results could be helpful to find a precise, global picture of thermal adaptation.

Crystal structure of the HMG domain of human BAF57 and its interaction with four-way junction DNA.

The SWI/SNF chromatin remodeling complex plays important roles in gene regulation and it is classified as the SWI/SNF complex in yeast and BAF complex in vertebrates. BAF57, one of the subunits that forms the chromatin remodeling complex core, is well conserved in the BAF complex of vertebrates, which is replaced by bap111 in the Drosophila BAP complex and does not have a counterpart in the yeast SWI/SNF complex. This suggests that BAF57 is a key component of the chromatin remodeling complex in higher eukaryotes. BAF57 contains a HMG domain, which is widely distributed among various proteins and functions as a DNA binding motif. Most proteins with HMG domain bind to four-way junction (4WJ) DNA. Here, we report the crystal structure of the HMG domain of BAF57 (BAF57HMG) at a resolution of 2.55 Å. The structure consists of three α-helices and adopts an L-shaped form. The overall structure is stabilized by a hydrophobic core, which is formed by hydrophobic residues. The binding affinity between BAF57HMG and 4WJ DNA is determined as a 295.83 ± 1.05 nM using a fluorescence quenching assay, and the structure revealed 4WJ DNA binding site of BAF57HMG. Our data will serve structural basis in understanding the roles of BAF57 during chromatin remodeling process.

Downhill, Ultrafast and Fast Folding Proteins Revised.

Research on the protein folding problem differentiates the protein folding process with respect to the duration of this process. The current structure encoded in sequence dogma seems to be clearly justified, especially in the case of proteins referred to as fast-folding, ultra-fast-folding or downhill. In the present work, an attempt to determine the characteristics of this group of proteins using fuzzy oil drop model is undertaken. According to the fuzzy oil drop model, a protein is a specific micelle composed of bi-polar molecules such as amino acids. Protein folding is regarded as a spherical micelle formation process. The presence of covalent peptide bonds between amino acids eliminates the possibility of free mutual arrangement of neighbors. An example would be the construction of co-micelles composed of more than one type of bipolar molecules. In the case of fast folding proteins, the amino acid sequence represents the optimal bipolarity system to generate a spherical micelle. In order to achieve the native form, it is enough to have an external force field provided by the water environment which directs the folding process towards the generation of a centric hydrophobic core. The influence of the external field can be expressed using the 3D Gaussian function which is a mathematical model of the folding process orientation towards the concentration of hydrophobic residues in the center with polar residues exposed on the surface. The set of proteins under study reveals a hydrophobicity distribution compatible with a 3D Gaussian distribution, taken as representing an idealized micelle-like distribution. The structure of the present hydrophobic core is also discussed in relation to the distribution of hydrophobic residues in a partially unfolded form.

The Structure of Amyloid Versus the Structure of Globular Proteins.

The issue of changing the structure of globular proteins into an amyloid form is in the focus of researchers' attention. Numerous experimental studies are carried out, and mathematical models to define the essence of amyloid transformation are sought. The present work focuses on the issue of the hydrophobic core structure in amyloids. The form of ordering the hydrophobic core in globular proteins is described by a 3D Gaussian distribution analog to the distribution of hydrophobicity in a spherical micelle. Amyloid fibril is a ribbon-like micelle made up of numerous individual chains, each representing a flat structure. The distribution of hydrophobicity within a single chain included in the fibril describes the 2D Gaussian distribution. Such a description expresses the location of polar residues on a circle with a center with a high level of hydrophobicity. The presence of this type of order in the amyloid forms available in Preotin Data Bank (PDB) (both in proto- and superfibrils) is demonstrated in the present work. In this system, it can be assumed that the amyloid transformation is a chain transition from 3D Gauss ordering to 2D Gauss ordering. This means changing the globular structure to a ribbon-like structure. This observation can provide a simple mathematical model for simulating the amyloid transformation of proteins.

Conserved 2nd Residue of Helix 8 of GPCR May Confer the Subclass-Characteristic and Distinct Roles through a Rapid Initial Interaction with Specific G Proteins.

To obtain a systematic view of the helix-8-second residue responsible for G protein-coupled receptor (GPCR)­G protein initial specific interactions, 786 human GPCRs were subclassified based on the pairs of agonist groups and target G proteins and compared with their conserved second residue of helix 8. Of 314 non-olfactory and deorphanized GPCRs, 273 (87%) conserved single amino acids in the subclasses, while 93 (58%) of the 160 subclasses possessed only a single GPCR member. Class B, C, Frizzled, and trace amine-associated GPCRs demonstrated 100% conservation, whereas class Ⅰ and Ⅱ olfactory and vomeronasal 1 receptors demonstrated much lower rates of conservation (20­47%). These conserved residues are characteristic of GPCR classes and G protein subtypes and confer their functionally-distinct roles.

The Amyloid as a Ribbon-Like Micelle in Contrast to Spherical Micelles Represented by Globular Proteins.

Selected amyloid structures available in the Protein Data Bank have been subjected to a comparative analysis. Classification is based on the distribution of hydrophobicity in amyloids that differ with respect to sequence, chain length, the distribution of beta folds, protofibril structure, and the arrangement of protofibrils in each superfibril. The study set includes the following amyloids: Aß (1-42), which is listed as Aß (15-40) and carries the D23N mutation, and Aß (11-42) and Aß (1-40), both of which carry the E22Δ mutation, tau amyloid, and α-synuclein. Based on the fuzzy oil drop model (FOD), we determined that, despite their conformational diversity, all presented amyloids adopt a similar structural pattern that can be described as a ribbon-like micelle. The same model, when applied to globular proteins, results in structures referred to as "globular micelles," emerging as a result of interactions between the proteins' constituent residues and the aqueous solvent. Due to their composition, amyloids are unable to attain entropically favorable globular forms and instead attempt to limit contact between hydrophobic residues and water by producing elongated structures. Such structures typically contain quasi hydrophobic cores that stretch along the fibril's long axis. Similar properties are commonly found in ribbon-like micelles, with alternating bands of high and low hydrophobicity emerging as the fibrils increase in length. Thus, while globular proteins are generally consistent with a 3D Gaussian distribution of hydrophobicity, the distribution instead conforms to a 2D Gaussian distribution in amyloid fibrils.

Variability of the core geometry in parallel coiled-coil bundles.

In protein modelling and design, an understanding of the relationship between sequence and structure is essential. Using parallel, homotetrameric coiled-coil structures as a model system, we demonstrated that machine learning techniques can be used to predict structural parameters directly from the sequence. Coiled coils are regular protein structures, which are of great interest as building blocks for assembling larger nanostructures. They are composed of two or more alpha-helices wrapped around each other to form a supercoiled bundle. The coiled-coil bundles are defined by four basic structural parameters: topology (parallel or antiparallel), radius, degree of supercoiling, and the rotation of helices around their axes. In parallel coiled coils the latter parameter, describing the hydrophobic core packing geometry, was assumed to show little variation. However, we found that subtle differences between structures of this type were not artifacts of structure determination and could be predicted directly from the sequence. Using this information in modelling narrows the structural parameter space that must be searched and thus significantly reduces the required computational time. Moreover, the sequence-structure rules can be used to explain the effects of point mutations and to shed light on the relationship between hydrophobic core architecture and coiled-coil topology.

Engineering Escherichia coli membrane phospholipid head distribution improves tolerance and production of biorenewables.

Economically competitive microbial production of biorenewable fuels and chemicals is often impeded by toxicity of the product to the microbe. Membrane damage is often identified as a major mechanism of this toxicity. Prior efforts to strengthen the microbial membrane by changing the phospholipid distribution have largely focused on the fatty acid tails. Herein, a novel strategy of phospholipid head engineering is demonstrated in Escherichia coli. Specifically, increasing the expression of phosphatidylserine synthase (+pssA) was found to significantly increase both the tolerance and production of octanoic acid, a representative membrane-damaging solvent. Tolerance of other industrially-relevant inhibitors, such as furfural, acetate, toluene, ethanol and low pH was also increased. In addition to the increase in the relative abundance of the phosphoethanolamine (PE) head group in the +pssA strain, there were also changes in the fatty acid tail composition, resulting in an increase in average length, percent unsaturation and decreased abundance of cyclic rings. This +pssA strain had significant changes in: membrane integrity, surface potential, electrochemical potential and hydrophobicity; sensitivity to intracellular acidification; and distribution of the phospholipid tails, including an increase in average length and percent unsaturation and decreased abundance of cyclic rings. Molecular dynamics simulations demonstrated that the +PE membrane had increased resistance to penetration of ethanol into the hydrophobic core and also the membrane thickness. Further hybrid models in which only the head group distribution or fatty acid tail distribution was altered showed that the increase in PE content is responsible for the increase in bilayer thickness, but the increased hydrophobic core thickness is due to altered distribution of both the head groups and fatty acid tails. This work demonstrates the importance of consideration of the membrane head groups, as well as a modeling approach, in membrane engineering efforts.

Surfactant-enhanced remediation of polycyclic aromatic hydrocarbons: A review.

Polycyclic aromatic hydrocarbons (PAHs) are toxic, mutagenic and carcinogenic organic compounds that are widely present in the environment. The bioremediation of PAHs is an economical and environmentally friendly remediation technique, but it is limited because PAHs have low water solubility and fewer bioavailable properties. The solubility and bioavailability of PAHs can be increased by using surfactants to reduce surface tension and interfacial tension; this method is called surfactant-enhanced remediation (SER). The SER of PAHs is influenced by many factors such as the type and concentration of surfactants, PAH hydrophobicity, temperature, pH, salinity, dissolved organic matter and microbial community. Furthermore, as mixed micelles have a synergistic effect on PAH solubilisation, selecting the optimum ratio of mixed surfactants leads to effective PAH remediation. Although the use of surfactants inhibits microbial activities in some cases, this could be avoided by choosing an optimum combination of surfactants and a proper microbial community for the targeted PAH(s), resulting in up to 99.99% PAH removal. This article reviews the literature on SER of PAHs, including surfactant types, the synergistic effect of mixed micelles on PAH removal, the impact of surfactants on the PAH biodegradation process, factors affecting the SER process, and the mechanisms of surfactant-enhanced solubilisation of PAHs.

A conserved tryptophan (W91) at the barrel-lid junction modulates the packing and stability of Kunitz (STI) family of inhibitors.

ß-trefoil fold, consisting of a six stranded ß-barrel capped at one end by a lid comprising of another six ß-strands, is one of the most important folds among proteins. Important classes of proteins like Interleukins (ILs), Fibroblast Growth Factors (FGFs), Kunitz (STI) family of inhibitors etc. belong to this fold. Their core is packed by hydrophobic residues contributed by the 6 stranded ß-barrel and three ß-hairpins that make essential contacts with each other and keep the protein in 'topologically minimal frustrated state'. A complete database analysis of the core residues of the ß-trefoil fold proteins presented here identified a conserved tryptophan (W91) residue in the Kunitz (STI) family of inhibitors that projects from the lid and interacts with the bottom layer residues of the barrel. This kind of interactions is unique in Kunitz (STI) family because no other families of ß-trefoil fold have such a shear sized residue at the barrel lid junction; suggesting its possible importance in packing and stability. We took WCI as a representative of this family and prepared four cavity creating mutants W91F-WCI, W91M-WCI, W91I-WCI & W91A-WCI. CD experiments show that the secondary structure of the mutants remains indistinguishable with the wild type. Crystal structures of the mutants W91F-WCI, W91M-WCI & W91A-WCI also show the same feature. However, slight readjustments of the side chains around the site of mutation have been observed so as to minimize the cavity created due to mutation. Comparative stability of these mutants, estimated using heat denaturation CD spectroscopy, indicates that stability of the mutants inversely correlates with the size of the cavity inside the core. Interestingly, although we mutated at the core, mutants show varying susceptibility against tryptic digestion that grossly follow their instability determined by CD. Our findings suggest that the W91 residue plays an important role in determining the stability and packing of the core of WCI.

Polymeric Micelles: Recent Advancements in the Delivery of Anticancer Drugs.

Nanotechnology, in health and medicine, extensively improves the safety and efficacy of different therapeutic agents, particularly the aspects related to drug delivery and targeting. Among various nano-carriers, polymer based macromolecular approaches have resulted in improved drug delivery for the diseases like cancers, diabetes, autoimmune disorders and many more. Polymeric micelles consisting of hydrophilic exterior and hydrophobic core have established a record of anticancer drug delivery from the laboratory to commercial reality. The nanometric size, tailor made functionality, multiple choices of polymeric micelle synthesis and stability are the unique properties, which have attracted scientists and researchers around the world to work upon in this opportunistic drug carrier. The capability of polymeric micelles as nano-carriers are nowhere less significant than nanoparticles, liposomes and other nanocarriers, as per as the commercial feasibility and presence is concerned. In fact polymeric micelles are among the most extensively studied delivery platforms for the effective treatment of different cancers as well as non-cancerous disorders. The present review highlights the sequential and recent developments in the design, synthesis, characterization and evaluation of polymeric micelles to achieve the effective anticancer drug delivery. The future possibilities and clinical outcome have also been discussed, briefly.

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes.

The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area. The hydrophobic properties of interfaces vary depending on the status of interacting domains-In this context we can distinguish: (1) Shared hydrophobic cores (spanning the whole dimer); (2) Individual hydrophobic cores present in each monomer irrespective of whether the dimer contains a shared core. Analysis of interfaces in dystrophin and utrophin indicates the presence of an additional quasi-domain with a prominent hydrophobic core, consisting of fragments contributed by both monomers. In addition, we have also attempted to determine the relationship between the type of interface (as categorized above) and the biological function of each complex. This analysis is entirely based on the fuzzy oil drop model.

The fuzzy oil drop model, based on hydrophobicity density distribution, generalizes the influence of water environment on protein structure and function.

In this paper we show that the fuzzy oil drop model represents a general framework for describing the generation of hydrophobic cores in proteins and thus provides insight into the influence of the water environment upon protein structure and stability. The model has been successfully applied in the study of a wide range of proteins, however this paper focuses specifically on domains representing immunoglobulin-like folds. Here we provide evidence that immunoglobulin-like domains, despite being structurally similar, differ with respect to their participation in the generation of hydrophobic core. It is shown that ß-structural fragments in ß-barrels participate in hydrophobic core formation in a highly differentiated manner. Quantitatively measured participation in core formation helps explain the variable stability of proteins and is shown to be related to their biological properties. This also includes the known tendency of immunoglobulin domains to form amyloids, as shown using transthyretin to reveal the clear relation between amyloidogenic properties and structural characteristics based on the fuzzy oil drop model.

Molecular Mechanisms Involved in the B Cell Growth and Clonogenic Activity of HIV-1 Matrix Protein p17 Variants.

The human immunodeficiency virus (HIV-1) matrix protein p17 (p17) is released from infected cells as a protein capable of deregulating the biological activity of different cells. P17 variants (vp17s), more frequently detected in the plasma of HIV-1+ patients with rather than without lymphoma and characterized by amino acids insertions in their C-terminal region, were found to trigger B cell growth and clonogenicity. Vp17s endowed with B-cell-growth-promoting activity are drastically destabilized, whereas, in a properly folded state, reference p17 (refp17) does not exert any biological activity on B cell growth and clonogenicity. However, misfolding of refp17 is necessary to expose a masked functional epitope, interacting with the protease-activated receptor 1 (PAR-1), endowed with B cell clonogenicity. Indeed, it is worth noting that changes in the secondary structure can strongly impact the function of a protein. Here, we performed computational studies to show that the gain of function of vp17s is linked to dramatic conformational changes due to structural modification in the secondary-structure elements and in the rearrangement of the hydrogen bond (H-bond) network. In particular, all clonogenic vp17s showed the disengagement of two critical residues, namely Trp16 and Tyr29, from their hydrophobic core. Biological data showed that the mutation of Trp16 and Tyr29 to Ala in the refp17 backbone, alone or in combination, resulted in a protein endowed with B cell clonogenic activity. These data show the pivotal role of the hydrophobic component in maintaining refp17 stability and identify a novel potential therapeutic target to counteract vp17-driven lymphomagenesis in HIV-1+ patients.

Structural Specificity of Polymorphic Forms of α-Synuclein Amyloid.

The structural transformation producing amyloids is a phenomenon that sheds new light on the protein folding problem. The analysis of the polymorphic structures of the α-synuclein amyloid available in the PDB database allows analysis of the amyloid-oriented structural transformation itself, but also the protein folding process as such. The polymorphic amyloid structures of α-synuclein analyzed employing the hydrophobicity distribution (fuzzy oil drop model) reveal a differentiation with a dominant distribution consistent with the micelle-like system (hydrophobic core with polar shell). This type of ordering of the hydrophobicity distribution covers the entire spectrum from the example with all three structural units (single chain, proto-fibril, super-fibril) exhibiting micelle-like form, through gradually emerging examples of local disorder, to structures with an extremely different structuring pattern. The water environment directing protein structures towards the generation of ribbon micelle-like structures (concentration of hydrophobic residues in the center of the molecule forming a hydrophobic core with the exposure of polar residues on the surface) also plays a role in the amyloid forms of α-synuclein. The polymorphic forms of α-synuclein reveal local structural differentiation with a common tendency to accept the micelle-like structuralization in certain common fragments of the polypeptide chain of this protein.