This work discusses the role of unstructured polypeptide chain fragments in shaping the protein's hydrophobic core. Based on the "fuzzy oil drop" model, which assumes an idealized distribution of hydrophobicity density described by the 3D Gaussian, we can determine which fragments make up the core and pinpoint residues whose location conflicts with theoretical predictions. We show that the structural influence of the water environment determines the positions of disordered fragments, leading to the formation of a hydrophobic core overlaid by a hydrophilic mantle. This phenomenon is further described by studying selected proteins which are known to be unstable and contain intrinsically disordered fragments. Their properties are established quantitatively, explaining the causative relation between the protein's structure and function and facilitating further comparative analyses of various structural models.
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 ?-structural fragments in ?-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.
The "fuzzy oil drop" model assumes that the idealized hydrophobic core in a protein body can be described by a 3D Gauss function. The structure of the 1ICF protein (cathepsin), which participates in the proteolysis process and has cysteine-type peptidase activity, has been analyzed on the basis of the "fuzzy oil drop" model. The authors have determined the contribution of individual exon fragments to the creation of a common hydrophobic core and assessed the involvement of each chain in this process, depending on the number of complexed chains. Quantitative assessment of exons, chains, dimers, and the whole complex suggest that each of these units plays a different role in shaping the proteins hydrophobic core.
This paper discusses the structural role of fragments encoded by individual exons in proteins. Selected enzymes (hydrolases, transferases, ligases) reveal the presence of at least one exon fragment whose contribution to the proteins hydrophobic core is in line with theoretical expectations. This phenomenon is confirmed by quantitative analysis of the hydrophobicity density distribution in protein molecules. Results are compared with a 3D Gaussian function, treated as an "idealized" distribution of hydrophobicity density, with the highest values observed near the center of the molecule and near-zero values on its surface. At least one accordant exon fragment has been identified in each of the proteins subjected to analysis. On the basis of these results the authors propose that accordant exons are responsible for tertiary structural stabilization of proteins by ensuring the generation of a stable hydrophobic core.
The characteristic distribution of non-binding interactions in a protein is described. It establishes that hydrophobic interactions can be characterized by suitable 3D Gauss functions while electrostatic interactions generally follow a random distribution. The implementation of this observation suggests differentiated optimization procedure for these two types of interactions. The electrostatic interaction may follow traditional energy optimization while the criteria for convergence shall measure the accordance with 3-D Gauss function.
The paper presents a model for simulating the protein folding process in silico. The two-step model (which consists of the early stage-ES and the late stage-LS) is verified using two proteins, one of which is treated (according to experimental observations) as the early stage and the second as an example of the LS step. The early stage is based solely on backbone structural preferences, while the LS model takes into account the water environment, treated as an external hydrophobic force field and represented by a 3D Gauss function. The characteristics of 1ZTR (the ES intermediate, as compared with 1ENH, which is the LS intermediate) confirm the link between the gradual disappearance of ES characteristics in LS structural forms and the simultaneous emergence of LS properties in the 1ENH protein. Positive verification of ES and LS characteristics in these two proteins (1ZTR and 1ENH respectively) suggest potential applicability of the presented model to in silico protein folding simulations.
Mutations in proteins introduce structural changes and influence biological activity: the specific effects depend on the location of the mutation. The simple method proposed in the present paper is based on a two-step model of in silico protein folding. The structure of the first intermediate is assumed to be determined solely by backbone conformation. The structure of the second one is assumed to be determined by the presence of a hydrophobic center. The comparable structural analysis of the set of mutants is performed to identify the mutant-induced structural changes. The changes of the hydrophobic core organization measured by the divergence entropy allows quantitative comparison estimating the relative structural changes upon mutation. The set of antifreeze proteins, which appeared to represent the hydrophobic core structure accordant with "fuzzy oil drop" model was selected for analysis.
The "fuzzy oil drop" model assuming the structure of the hydrophobic core of the form of 3-D Gauss function appeared to be verified positively. The protein 1NMF belonging to downhill proteins was found to represent the hydrophobic density distribution accordant with the assumed model. The accordance of the protein structure with the assumed model was measured using elements of theory information. This observation opens the possibility to simulate the folding process as influenced by external force field of hydrophobic character.
The identification of the surface area able to generate the protein-protein complexation ligand and ion ligation is critical for the recognition of the biological function of particular proteins. The technique based on the analysis of the irregularity of hydrophobicity distribution is used as the criterion for the recognition of the interaction regions. Particularly, the exposure of hydrophobic residues on the surface of protein as well as the localization of the hydrophilic residues in the hydrophobic core is treated as potential area ready to interact with external molecules. The model based on the "fuzzy oil drop" approach treating the protein molecule as the drop of hydrophobicity concentrated in the central part of structure with the hydrophobicity close to zero on the surface according to 3-dimensional Gauss function. The comparison with the observed hydrophobicy in particular protein reveals some irregularities. These irregularities seem to represent the aim-oriented localization.
The multi sub-unit protein structure representing the chaperonins group is analyzed with respect to its hydrophobicity distribution. The proteins of this group assist protein folding supported by ATP. The specific axial symmetry GroEL structure (two rings of seven units stacked back to back - 524 aa each) and the GroES (single ring of seven units - 97 aa each) polypeptide chains are analyzed using the hydrophobicity distribution expressed as excess/deficiency all over the molecule to search for structure-to-function relationships. The empirically observed distribution of hydrophobic residues is confronted with the theoretical one representing the idealized hydrophobic core with hydrophilic residues exposure on the surface. The observed discrepancy between these two distributions seems to be aim-oriented, determining the structure-to-function relation. The hydrophobic force field structure generated by the chaperonin capsule is presented. Its possible influence on substrate folding is suggested.
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