Ligation site in proteins recognized in silico

Recognition of a ligation site in a protein molecule is important for identifying its biological activity. The model for in silico recognition of ligation sites in proteins is presented. The idealized hydrophobic core stabilizing protein structure is represented by a three-dimensional Gaussian function. The experimentally observed distribution of hydrophobicity compared with the theoretical distribution reveals differences. The area of high differences indicates the ligation site

The Influence of Proteins Surface on the Ordering of Surrounded Water

Protein folding remains not satisfactory understood process. Considering the critical importance of water for proteins and other biologically active molecules, analysis of water-protein interactions should play a central role in studies concerning the folding process and biological activity of proteins. Folding simulations should acknowledge the aqueous solvent as an active partner which determines the final conformation of a protein. In the fuzzy oil drop model (which is applied in the presented analysis), the solvent is treated as a continuum—an external force field guiding the folding process. This interaction goes both ways: (1) the solvent shapes the protein and (2) the presence of a natively folded protein also alters the structure of the solvent (the structure of water has not heretofore been sufficiently studied—except for the solid state). This work focuses on this second reverse relationship, that is, the influence of proteins upon the structuralization of water. We formulate a hypothesis which is based on the fuzzy oil drop model. The ordering of the hydrophobic core which resides inside the protein and may include local discordances is analyzed from the point of view of its external effects. In accordance to the fuzzy oil drop model, the solvent is expected to “react” to local differentiation in the properties of the molecular surface. Our hypothesis remains speculative, since experimental studies have not yet yielded sufficient evidence to either prove or disprove it. The presented analysis bases on the assumption that a protein is nothing more than a tool engineered to perform a specific task. Thus, the protein’s structure must encode its intended use and the inter-molecular communication system. Our study focuses on antifreeze proteins, which are particularly interesting since their function involves altering the properties of the solvent—specifically, preventing the formation of ice crystals

Propagation of fibrillar structural forms in proteins stopped by naturally occurring short polypeptide chain fragments

Amyloids characterized by unbounded growth of fibrillar structures cause many pathological processes. Such unbounded propagation is due to the presence of a propagating hydrophobicity field around the fibril’s main axis, preventing its closure (unlike in globular proteins). Interestingly, similar fragments, commonly referred to as solenoids, are present in many naturally occurring proteins, where their propagation is arrested by suitably located “stopper” fragments. In this work, we analyze the distribution of hydrophobicity in solenoids and in their corresponding “stoppers” from the point of view of the fuzzy oil drop model (called FOD in this paper). This model characterizes the unique linear propagation of local hydrophobicity in the solenoid fragment and allows us to pinpoint “stopper” sequences, where local hydrophobicity quite closely resembles conditions encountered in globular proteins. Consequently, such fragments perform their function by mediating entropically advantageous contact with the water environment. We discuss examples of amyloid-like structures in solenoids, with particular attention to “stop” segments present in properly folded proteins found in living organisms

Why do antifreeze proteins require a solenoid?

Proteins whose presence prevents water from freezing in living organisms at temperatures below 0 C are referred to as antifreeze proteins. This group includes molecules of varying size (from 30 to over 300 aa) and variable secondary/supersecondary conformation. Some of these proteins also contain peculiar structural motifs called solenoids. We have applied the fuzzy oil drop model in the analysis of four categories of antifreeze proteins: 1 e very small proteins, i.e. helical peptides (below 40 aa); 2 e small globular proteins (40e100 aa); 3 e large globular proteins (>100 aa) and 4 e proteins containing solenoids. The FOD model suggests a mechanism by which antifreeze proteins prevent freezing. In accordance with this theory, the presence of the protein itself produces an ordering of water molecules which counteracts the formation of ice crystals. This conclusion is supported by analysis of the ordering of hydrophobic and hydrophilic residues in antifreeze proteins, revealing significant variability e from perfect adherence to the fuzzy oil drop model through structures which lack a clearly defined hydrophobic core, all the way to linear arrangement of alternating local minima and maxima propagating along the principal axis of the solenoid (much like in amyloids). The presented model e alternative with respect to the ice docking model e explains the antifreeze properties of compounds such as saccharides and fatty acids. The fuzzy oil drop model also enables differentiation between amyloids and antifreeze proteins

Towards the design of anti-amyloid short peptide helices

A set of short peptide sequences susceptible to fibrillar aggregation produces sequneces capable of arresting elongation of amyloid fibrils. The "stop" signals are short helices customized for each individual target. Such a helix should exhibit high amphiphilicity, with differing conditions present on each side (one side should be highly hydrophilic to enable water to interact with the aggregate, while the other side must retain a local distribution of hydrophobicity which matches that of the terminal portion of the fibril). The emergence and elongation of fibrillary forms resulting from linear propagation of local hydrophobicity peaks is shown using the fuzzy oil drop model

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: $A\beta$ (1-42), which is listed as $A\beta$ (15-40) and carries the D23N mutation, and $A\beta$ (11-42) and $A\beta$ (1-40), both of which carry the $E22\Delta$ mutation, tau amyloid, and $\alpha$-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

Application of the fuzzy oil drop model describes amyloid as a ribbonlike micelle

We propose a mathematical model describing the formation of micellar forms—whether spherical, globular, cylindrical, or ribbonlike—as well as its adaptation to protein structure. Our model, based on the fuzzy oil drop paradigm, assumes that in a spherical micelle the distribution of hydrophobicity produced by the alignment of polar molecules with the external water environment can be modeled by a 3D Gaussian function. Perturbing this function by changing the values of its sigma parameters leads to a variety of conformations—the model is therefore applicable to globular, cylindrical, and ribbonlike micelles. In the context of protein structures ranging from globular to ribbonlike, our model can explain the emergence of fibrillar forms; particularly amyloids

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 \beta -structural fragments in \beta -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