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Proteins adopt a specific spatial organization, most often called a “structure”. This structure is crucial for their function. This relationship between structure and function, established by Emil Fisher at the end of the 19th century, is the foundation of structural biology. Methods used for determining the structure of proteins have evolved considerably, but the method of choice remains as X-ray diffraction, which requires the protein to be crystallized. The data bank listing protein structures (as well as nucleic acids and some sugars) is the PDB (Protein Data Bank) (Berman et al. 2000). The number of resolved protein structures is growing rapidly from year to year. A protein could theoretically adopt a large number of three-dimensional conformations, but most of them spontaneously fold into a particular and unique stable form. This particular shape is due to the fact that the peptide backbone groups and side chains interact with each other and with water. Thus, some conformations have more stabilizing interactions than others and are therefore favored (Alberts et al. 1994). The paradigm of the relationship between the protein sequence and its three-dimensional (3D) structure comes from Christian Anfinsen’s studies on ribonuclease (Anfinsen 1973). Anfinsen showed that proteins isolated in solution can regain their original active conformation after denaturation. Therefore, the conclusion was that all the information needed to fold a protein must be inherent to its amino acid order (Alberts et al. 1994). Other studies have also drawn the same conclusions, leading to the general theory that the amino acid sequence of a protein specifies its conformation (Stryer 1994).

“Water-soluble” proteins fold into a compact globular form (unlike fibrous, membrane and “disordered” proteins). The hydrophobic nature of certain amino acids makes this compact folding necessary. Indeed, the side chains of the non-polar residues are hydrophobic and are grouped together within the globular structure of the protein – isolated from the surrounding water – while the polar residues, and the polar groups of the backbone, are hydrophilic and form hydrogen bonds with water or with each other. This spatial distribution of hydrophobicity has been known since the middle of the 20th century, in particular thanks to the work of Bressler and Talmud (1944), who described a globular protein as a micelle, with a predominantly hydrophobic core surrounded by a predominantly hydrophilic crown. The hydrophobic and hydrogen bonds are largely responsible for the stability of the protein structure, obtained under the effect of the only available energy source, thermal agitation. These continuous fluctuations lead to more or less rapid displacements around stable local conformations, called secondary structures. Alpha helices (30% of the residues) and beta strands (20% of the residues) are the most frequent. These local structures are stabilized by hydrogen bonds due to the particular values of the dihedral angles of the peptide backbone.