Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is different from the inverse problem of protein design. Protein structure prediction is one of the most important goals pursued by computational biology and addresses Levinthal's paradox. Accurate structure prediction has important applications in medicine (for example, in drug design) and biotechnology (for example, in novel enzyme design). Starting in 1994, the performance of current methods is assessed biennially in the Critical Assessment of Structure Prediction (CASP) experiment. A continuous evaluation of protein structure prediction web servers is performed by the community project Continuous Automated Model EvaluatiOn (CAMEO3D).
Protein structure and Terminology Proteins are chains of amino acids joined together by peptide bonds. Many conformations of this chain are possible due to the rotation of the main chain about the two torsion angles φ and ψ at the Cα atom. This conformational flexibility is responsible for differences in the three-dimensional structure of proteins.
The peptide bonds in the chain are polar, i.e. they have separated positive and negative charges (partial charges) in the carbonyl group, which can act as hydrogen bond acceptor and in the NH group, which can act as hydrogen bond donor. These groups can therefore interact in the protein structure. Proteins consist mostly of 20 different types of L-α-amino acids (the proteinogenic amino acids). These can be classified according to the chemistry of the side chain, which also plays an important structural role. Glycine takes on a special position, as it has the smallest side chain, only one hydrogen atom, and therefore can increase the local flexibility in the protein structure. Cysteine in contrast can react with another cysteine residue to form one cystine and thereby form a cross link stabilizing the whole structure. Protein structure arises from a sequence of secondary structure elements, such as α helices and β sheets. In secondary structures, regular patterns of H-bonds are formed between the main chain NH and CO groups of spatially neighboring amino acids, and the amino acids have similar Φ and ψ angles.
Formation of these secondary structures efficiently satisfies the hydrogen bonding capacities of the peptide bonds. The secondary structures can be tightly packed in the protein core in a hydrophobic environment, but they can also be present at a polar protein surface. Each amino acid side chain has a limited volume to occupy and a limited number of possible interactions with other nearby side chains, a situation that must be taken into account in molecular modeling and alignments.
α-helix
The α-helix is the most abundant type of secondary structure in proteins. The α-helix has 3.6 amino acids per turn with an H-bond formed between every fourth residue; the average length is 10 amino acids (3 turns) or 10 Å but varies from 5 to 40 (1.5 to 11 turns). The alignment of the H-bonds creates a dipole moment for the helix with a resulting partial positive charge at the amino end of the helix. Because this region has free NH2 groups, it will interact with negatively charged groups such as phosphates. The most common location of α-helices is at the surface of protein cores, where they provide an interface with the aqueous environment. The inner-facing side of the helix tends to have hydrophobic amino acids and the outer-facing side hydrophilic amino acids. Thus, every third of four amino acids along the chain will tend to be hydrophobic, a pattern that can be quite readily detected. In the leucine zipper motif, a repeating pattern of leucines on the facing sides of two adjacent helices is highly predictive of the motif. A helical-wheel plot can be used to show this repeated pattern. Other α-helices buried in the protein core or in cellular membranes have a higher and more regular distribution of hydrophobic amino acids, and are highly predictive of such structures. Helices exposed on the surface have a lower proportion of hydrophobic amino acids. Amino acid content can be predictive of an α-helical region. Regions richer in alanine (A), glutamic acid (E), leucine (L), and methionine (M) and poorer in proline (P), glycine (G), tyrosine (Y), and serine (S) tend to form an α-helix. Proline destabilizes or breaks an α-helix but can be present in longer helices, forming a bend.
β-sheet
β-sheets are formed by H-bonds between an average of 5–10 consecutive amino acids in one portion of the chain with another 5–10 farther down the chain. The interacting regions may be adjacent, with a short loop in between, or far apart, with other structures in between. Every chain may run in the same direction to form a parallel sheet, or in the reverse direction to form an antiparallel sheet, or the chains may form a mixed sheet. The pattern of hydrogen bonding is different in the parallel and antiparallel configurations. Each amino acid in the interior strands of the sheet forms two H-bonds with neighboring amino acids, whereas each amino acid on the outside strands forms only one bond with an interior strand. Looking across the sheet at right angles to the strands, more distant strands are rotated slightly counterclockwise to form a left-handed twist. The Cα-atoms alternate above and below the sheet in a pleated structure, and the R side groups of the amino acids alternate above and below the pleats. The Φ and Ψ angles of the amino acids in sheets vary considerably in one region of the Ramachandran plot. It is more difficult to predict the location of β-sheets than of α-helices. The situation improves somewhat when the amino acid variation in multiple sequence alignments is taken into account.
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