Background: Over the last few decades, a search for the theory of protein folding has grown into a full-fledged research field at the intersection of biology, chemistry and informatics. Despite enormous effort, there are still open questions and challenges, like understanding the rules by which amino acid sequence determines protein secondary structure. Objective: In this review, we depict the progress of the prediction methods over the years and identify sources of improvement. Methods: The protein secondary structure prediction problem is described followed by the discussion on theoretical limitations, description of the commonly used data sets, features and a review of three generations of methods with the focus on the most recent advances. Additionally, methods with available online servers are assessed on the independent data set. Results: The state-of-the-art methods are currently reaching almost 88% for 3-class prediction and 76.5% for an 8-class prediction. Conclusion: This review summarizes recent advances and outlines further research directions.

The neural correlates of face individuation—the acquisition of memory representations for novel faces—have been studied only in coarse detail and disregarding individual differences between learners. In their seminal study, Tanaka et al . (Tanaka et al. 2006 J. Cogn. Neurosci. 18 , 1488–1497. ( doi:10.1162/jocn.2006.18.9.1488 )) required the identification of a particular novel face across 70 trials and found that the N250 component in the EEG event-related potentials became more negative from the first to the second half of the experiment, where it reached a similar amplitude as a well-known face. We were unable to directly replicate this finding in our study when we used the original split of trials. However, when we applied a different split of trials we observed very similar changes in N250 amplitude. We conclude that the N250 component is indeed sensitive to the build-up of a robust representation of a face in memory; the time course of this process appears to vary as a function of variables that may be determined in future research.

The water environment determines the activity of biological processes. The role of such an environment interpreted in the form of an external field expressed by the 3D Gaussian distribution in the fuzzy oil drop model directs the folding process towards the generation of a centrally located hydrophobic core with the simultaneous exposure of polar residues on the surface. In addition to proteins soluble in the water environment, there is a significant group of membrane proteins that act as receptors or channels, including ion channels in particular. The change of the polar (water) environment into a highly hydrophobic (membrane) environment is quite radical, resulting in a different hydrophobicity distribution within the membrane protein. Modification of the notation of the force field expressing the presence of the hydrophobic environment has been proposed in this work. A modified fuzzy oil drop model with its adaptation to membrane proteins was used to interpret the structure of membrane proteins–mechanosensitive channel. The modified model was also used to describe the so-called negative cases—i.e., for water-soluble proteins with a clear distribution consistent with the fuzzy oil drop model.

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.

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Four de novo proteins differing in single mutation positions, with a chain length of 56 amino acids, represent diverse 3D structures: monomeric 3α and 4β + α folds. The reason for this diversity is seen in the different structure of the hydrophobic core as a result of synergy leading to the generation of a system in which the polypeptide chain as a whole participates. On the basis of the fuzzy oil drop model, where the structure of the hydrophobic core is expressed by means of the hydrophobic distribution function in the form of a 3D Gaussian distribution, it has been shown that the composition of the hydrophobic core in these two structural forms is different. In addition, the use of a model to determine the structure of the early intermediate in the folding process allows to indicate differences in the polypeptide chain geometry, which, combined with the construction of a common hydrophobic nucleus as an effect of specific synergy, may indicate the reason for the diversity of the folding process of the polypeptide chain. The results indicate the need to take into account the presence of an external force field originating from the water environment and that its active impact on the formation of a hydrophobic core whose participation in the stabilization of the tertiary structure is fundamental.

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