Editing Protein structure prediction (section)

==Protein classification==

Proteins may be classified according to both structural and sequential similarity. For structural classification, the sizes and spatial arrangements of secondary structures described in the above paragraph are compared in known three-dimensional structures. Classification based on sequence similarity was historically the first to be used. Initially, similarity based on alignments of whole sequences was performed. Later, proteins were classified on the basis of the occurrence of conserved amino acid patterns. [[Databases]] that classify proteins by one or more of these schemes are available.
In considering protein classification schemes, it is important to keep several observations in mind. First, two entirely different protein sequences from different evolutionary origins may fold into a similar structure. Conversely, the sequence of an ancient gene for a given structure may have diverged considerably in different species while at the same time maintaining the same basic structural features. Recognizing any remaining sequence similarity in such cases may be a very difficult task. Second, two proteins that share a significant degree of sequence similarity either with each other or with a third sequence also share an evolutionary origin and should share some structural features also. However, gene duplication and genetic rearrangements during evolution may give rise to new gene copies, which can then evolve into proteins with new function and structure.<ref name="Mount"/>

===Terms used for classifying protein structures and sequences===<!-- These terms may vary in definition on different databases and resources. Do not rely on these definitions as correct. -->
The more commonly used terms for evolutionary and structural relationships among proteins are listed below. Many additional terms are used for various kinds of structural features found in proteins. Descriptions of such terms may be found at the CATH Web site, the [[Structural Classification of Proteins]] (SCOP) Web site, and a [[Glaxo Wellcome]] tutorial on the Swiss bioinformatics Expasy Web site.{{Cn|date=October 2024}}

;[[Active site]]: a localized combination of amino acid side groups within the tertiary (three-dimensional) or quaternary (protein subunit) structure that can interact with a chemically specific substrate and that provides the protein with biological activity. Proteins of very different amino acid sequences may fold into a structure that produces the same active site.
;Architecture: is the relative orientations of secondary structures in a three-dimensional structure without regard to whether or not they share a similar loop structure.
;Fold (topology): a type of architecture that also has a conserved loop structure.
;Blocks: is a conserved amino acid sequence pattern in a family of proteins. The pattern includes a series of possible matches at each position in the represented sequences, but there are not any inserted or deleted positions in the pattern or in the sequences. By way of contrast, sequence profiles are a type of scoring matrix that represents a similar set of patterns that includes insertions and deletions.
;[[protein fold class|Class]]: a term used to classify protein domains according to their secondary structural content and organization. Four [[protein fold class|classes]] were originally recognized by Levitt and Chothia (1976), and several others have been added in the SCOP database. Three classes are given in the CATH database: mainly-α, mainly-β, and α–β, with the α–β class including both alternating α/β and α+β structures.
;Core: the portion of a folded protein molecule that comprises the hydrophobic interior of α-helices and β-sheets. The compact structure brings together side groups of amino acids into close enough proximity so that they can interact. When comparing protein structures, as in the SCOP database, core is the region common to most of the structures that share a common fold or that are in the same superfamily. In structure prediction, core is sometimes defined as the arrangement of secondary structures that is likely to be conserved during evolutionary change.
;[[protein domain|Domain]] (sequence context): a segment of a polypeptide chain that can fold into a three-dimensional structure irrespective of the presence of other segments of the chain. The separate domains of a given protein may interact extensively or may be joined only by a length of polypeptide chain. A protein with several domains may use these domains for functional interactions with different molecules.
;[[protein family|Family]] (sequence context): a group of proteins of similar biochemical function that are more than 50% identical when aligned. This same cutoff is still used by the [[Protein Information Resource]] (PIR). A protein family comprises proteins with the same function in different organisms (orthologous sequences) but may also include proteins in the same organism (paralogous sequences) derived from gene duplication and rearrangements. If a multiple sequence alignment of a protein family reveals a common level of similarity throughout the lengths of the proteins, PIR refers to the family as a homeomorphic family. The aligned region is referred to as a homeomorphic domain, and this region may comprise several smaller homology domains that are shared with other families. Families may be further subdivided into subfamilies or grouped into superfamilies based on respective higher or lower levels of sequence similarity. The SCOP database reports 1296 families and the CATH database (version 1.7 beta), reports 1846 families.
:When the sequences of proteins with the same function are examined in greater detail, some are found to share high sequence similarity. They are obviously members of the same family by the above criteria. However, others are found that have very little, or even insignificant, sequence similarity with other family members. In such cases, the family relationship between two distant family members A and C can often be demonstrated by finding an additional family member B that shares significant similarity with both A and C. Thus, B provides a connecting link between A and C. Another approach is to examine distant alignments for highly conserved matches.
:At a level of identity of 50%, proteins are likely to have the same three-dimensional structure, and the identical atoms in the sequence alignment will also superimpose within approximately 1 Å in the structural model. Thus, if the structure of one member of a family is known, a reliable prediction may be made for a second member of the family, and the higher the identity level, the more reliable the prediction. Protein structural modeling can be performed by examining how well the amino acid substitutions fit into the core of the three-dimensional structure.
;Family (structural context): as used in the FSSP database ([[Families of structurally similar proteins]]) and the DALI/FSSP Web site, two structures that have a significant level of structural similarity but not necessarily significant sequence similarity.
;Fold: similar to structural motif, includes a larger combination of secondary structural units in the same configuration. Thus, proteins sharing the same fold have the same combination of secondary structures that are connected by similar loops. An example is the Rossman fold comprising several alternating α helices and parallel β strands. In the SCOP, CATH, and FSSP databases, the known protein structures have been classified into hierarchical levels of structural complexity with the fold as a basic level of classification.
;Homologous domain (sequence context): an extended sequence pattern, generally found by sequence alignment methods, that indicates a common evolutionary origin among the aligned sequences. A homology domain is generally longer than motifs. The domain may include all of a given protein sequence or only a portion of the sequence. Some domains are complex and made up of several smaller homology domains that became joined to form a larger one during evolution. A domain that covers an entire sequence is called the homeomorphic domain by PIR ([[Protein Information Resource]]).
;Module: a region of conserved amino acid patterns comprising one or more motifs and considered to be a fundamental unit of structure or function. The presence of a module has also been used to classify proteins into families.
;[[protein motif|Motif]] (sequence context): a conserved pattern of amino acids that is found in two or more proteins. In the [[Prosite]] catalog, a motif is an amino acid pattern that is found in a group of proteins that have a similar biochemical activity, and that often is near the active site of the protein. Examples of sequence motif databases are the Prosite catalog and the Stanford Motifs Database.<ref>{{cite journal |vauthors=Huang JY, Brutlag DL |date=January 2001 |title=The EMOTIF database |journal=Nucleic Acids Research |volume=29 |issue=1 |pages=202–4 |pmid=11125091 |pmc=29837 |doi=10.1093/nar/29.1.202}}</ref>
;Motif (structural context): a combination of several secondary structural elements produced by the folding of adjacent sections of the polypeptide chain into a specific three-dimensional configuration. An example is the helix-loop-helix motif. Structural motifs are also referred to as supersecondary structures and folds.
;[[Position-specific scoring matrix]] (sequence context, also known as weight or scoring matrix): represents a conserved region in a multiple sequence alignment with no gaps. Each matrix column represents the variation found in one column of the multiple sequence alignment.
;[[Position-specific scoring matrix]]—3D (structural context): represents the amino acid variation found in an alignment of proteins that fall into the same structural class. Matrix columns represent the amino acid variation found at one amino acid position in the aligned structures.
;[[Protein primary structure|Primary structure]]: the linear amino acid sequence of a protein, which chemically is a polypeptide chain composed of amino acids joined by peptide bonds.
;[[Sequence profiling tool|Profile (sequence context)]]: a scoring matrix that represents a multiple sequence alignment of a protein family. The profile is usually obtained from a well-conserved region in a multiple sequence alignment. The profile is in the form of a matrix with each column representing a position in the alignment and each row one of the amino acids. Matrix values give the likelihood of each amino acid at the corresponding position in the alignment. The profile is moved along the target sequence to locate the best scoring regions by a dynamic programming algorithm. Gaps are allowed during matching and a gap penalty is included in this case as a negative score when no amino acid is matched. A sequence profile may also be represented by a [[hidden Markov model]], referred to as a profile HMM.
;Profile (structural context): a scoring matrix that represents which amino acids should fit well and which should fit poorly at sequential positions in a known protein structure. Profile columns represent sequential positions in the structure, and profile rows represent the 20 amino acids. As with a sequence profile, the structural profile is moved along a target sequence to find the highest possible alignment score by a dynamic programming algorithm. Gaps may be included and receive a penalty. The resulting score provides an indication as to whether or not the target protein might adopt such a structure.
;[[protein quaternary structure|Quaternary structure]]: the three-dimensional configuration of a protein molecule comprising several independent polypeptide chains.
;[[protein secondary structure|Secondary structure]]: the interactions that occur between the C, O, and NH groups on amino acids in a polypeptide chain to form α-helices, β-sheets, turns, loops, and other forms, and that facilitate the folding into a three-dimensional structure.
;[[Protein superfamily|Superfamily]]: a group of protein families of the same or different lengths that are related by distant yet detectable sequence similarity. Members of a given [[protein superfamily|superfamily]] thus have a common evolutionary origin. Originally, Dayhoff defined the cutoff for superfamily status as being the chance that the sequences are not related of 10 6, on the basis of an alignment score (Dayhoff et al. 1978). Proteins with few identities in an alignment of the sequences but with a convincingly common number of structural and functional features are placed in the same superfamily. At the level of three-dimensional structure, superfamily proteins will share common structural features such as a common fold, but there may also be differences in the number and arrangement of secondary structures. The PIR resource uses the term ''homeomorphic superfamilies'' to refer to superfamilies that are composed of sequences that can be aligned from end to end, representing a sharing of single sequence homology domain, a region of similarity that extends throughout the alignment. This domain may also comprise smaller homology domains that are shared with other protein families and superfamilies. Although a given protein sequence may contain domains found in several superfamilies, thus indicating a complex evolutionary history, sequences will be assigned to only one homeomorphic superfamily based on the presence of similarity throughout a multiple sequence alignment. The superfamily alignment may also include regions that do not align either within or at the ends of the alignment. In contrast, sequences in the same family align well throughout the alignment.
;[[Protein tertiary structure|Supersecondary structure]]: a term with similar meaning to a structural motif. Tertiary structure is the three-dimensional or globular structure formed by the packing together or folding of secondary structures of a polypeptide chain.<ref name="Mount"/>