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1 LE STRUTTURE β

11 Antiparallel A residue in an antiparallel beta strand has values of -139 and +135 degrees for the backbone dihedral angles F and Y respectively. Antiparallel beta sheets are thought to be intrinsically more stable than parallel sheets due to the more optimal orientation of the interstrand hydrogen bonds. Parallel The hydrogen bonds in a parallel beta sheet are not perpendicular to the individual strands resulting in component (~1/3 of the peptide dipole) parallel to the strand. The parallel sheet then has an overall macrodipole leaving then an effective charge of ~ +1/15 unit elemental charge at the N- terminus and - 1/15 charge at the C-terminus of each strand of average length (~5 times less than an average alpha helix macrodipole).

Amfipaticità Antiparalleli quelli antiparalleli solitamente distribuiscono i

si trovano di preferenza sulla superficie delle proteine solubili Paralleli

i lati del foglietto, per cui queste strutture si trovano di preferenza all

12 Amfipaticità Antiparalleli quelli antiparalleli solitamente distribuiscono i residui idrofobici solo su di un lato del foglietto, quindi queste strutture si trovano di preferenza sulla superficie delle proteine solubili Paralleli quelli paralleli solitamente distribuiscono i residui non polari su entrambi i lati del foglietto, per cui queste strutture si trovano di preferenza all interno delle proteine solubili (o sulla superficie di proteine di membrana)

14 Strand connections There are two basic categories of connections between the individual strands of a beta sheet (Richardson, 1981). When the backbone enters the same end of the sheet that it left it is called a hairpin connection (beta turn) (a) and when the backbone enters the opposite end it is called a crossover connection (b). Crossover connections can be thought of as a type of helical connection of the strand ends. In globular proteins, righthanded crossovers are the rule, although a few examples of left-handed crossovers are available (e.g., subtilisin and glucose phosphate isomerase).

22 Type of TURNS A beta-turn is a region of the protein involving four consecutive residues where the polypeptide chain folds back on itself by nearly 180 degrees (Lewis et al. 1971, 1973; Kuntz 1972; Crawford et al. 1973; Chou and Fasman 1974). It is these chain reversals which give a protein its globularity rather than linearity. The ß-turn was originally identified, in model building studies, by Venkatachalam (1968). He proposed three distinct conformations based on phi,psi values (designated I,II and III) along with their related turns (mirror images)which have the phi, psi signs reversed (I',II' and III'), each of which could form a hydrogen bond between the main chain C=O(i) and the N- H(i+3). Subsequently, Lewis et al. (1973) examined the growing number ofthree-dimensional protein structures and suggested a more general definition of a ß-turn. This stated that the distance between the Calpha(i) and the Calpha(i+3) was < 7Å and the residues involved were not helical. They found that 25% of their extended ß-turns did not possess the intraturn hydrogen bond suggested by Venkatachalam. To include the new data they extended the classification of ß- turns to 10 distinct types (I,I',II,II',III,III',IV,V,VI and VII). These classes were defined not only by phi,psi angles, but also less stringent criteria. Hutchinson and Thornton (1994) has since reappraised the situation, and has suggested that there are 9 distinct types (I,I',II,II',IV, VIa1, VIa2, VIb and VIII) based on phi,psi ranges, along with a miscellaneous category IV. In present study, we have used this classification. The following table shows the nine beta-turn types with their dihedral angles: 22

23 N- ter Nomenclature for residues in hairpin beta-turns and phi psi angles C-ter I II I II

24 Dihedral angles of the last beta turn nomenclatur e N- ter C-ter i i+3 i+1 i+2 24

25 There are position dependent amino acid preferences for residues in turn conformations. Type I can tolerate all residues in positions i to i+3 with the exception of Pro at position i+2. Proline is favored at position i+1 and Gly is favored at i+3 in type I and II turns. The polar sidechains of Asn, Asp, Ser, and Cys often populate position i where they can hydrogen bond to the backbone NH of residue i+2. Ideally, type I' turns have Gly at positions i+1 and i+2 and type II' turns have Gly at position i+1 as the presence of a CB atom would cause a steric clash with the peptide carbonyl oxygen.

26 Type I turn. Note the hydrogen bond between CO of residue i and NH of residue i+3. The backbone dihedral angles of residue are (-60, -30) and (-90, 0) of residues i+1 and i+2, respectively of the type I turn. Proline is often found in position i+1 in type I turns as its phi angle is restricted to -60 and its imide nitrogen does not require a hydrogen bond. Glycine is favored in this position in the type II' as it requires a positive (left-handed) phi value.

27 Type II turn. Note the hydrogen bond between CO of residue i and NH of residue i+3. The backbone dihedral angles of residue are (-60, 120) and (80, 0) of residues i+1 and i+2, respectively of the type II turn. Proline is often found in position i+1 in type I turns as its phi angle is restricted to -60 and its imide nitrogen does not require a hydrogen bond. Glycine is favored in this position in the type II' as it requires a positive (left-handed) phi value.

31 Loops Leszczynski & Rose (1986) found a type of loop structure in what was previously classified as "random" conformation. In their survey of 67 proteins, they tabulated 26% Helix, 19% sheet, 26% turns and 21% in loops. These loop structures contain between 6 and 16 residues and are compact and globular in structure. Like turns, they generally contain polar residues and hence are predominantly at the protein surface.

Riepilogo sul ripiegamento β Permette alla catena peptidica di invertire la sua direzione Il C carbonilico di un residuo e legato, tramite legame-h, al protone amidico del residuo tre residui piu

32 Riepilogo sul ripiegamento β Permette alla catena peptidica di invertire la sua direzione Il C carbonilico di un residuo e legato, tramite legame-h, al protone amidico del residuo tre residui piu avanti La particolare conformazione dei ripiegamenti β dipende dagli aminoacidi che la compongono La prolina e la glicina sono i residui che prevalgono nei ripiegamenti β La pro ha una struttura ciclica e un angolo φ fisso che forza la formazione di un ripiegamento β e in molti casi questo facilita l inversione della direzione La gly e stericamente l aminoacido piu adattabile

33 OTHER SECONDARY STRUCTURE Approximately 80-90% of residues in globular proteins can be classified as participating in an alpha helix, beta sheet, or reverse turn. Exact numbers are difficult since defining the secondary structures themselves is a bit of a problem and will differ from survey to survey. However, a number of other secondary structures have been proposed. Even though structural characterization of these non-regular polypeptide segments is difficult, remember that most (>90%) potential backbone hydrogen bond donors and acceptors are involved in hydrogen bonds in solution. 46% of C=O and 68% of NH groups are involved in backbonebackbone hydrogen bonds and 15% and 10%, respectively involve sidechain atoms.

36 Paperclips Milner-White (1988) has extended the classification of helical C- terminal "caps" in his identification of "paperclips". These paperclips occur frequently, but not exclusively at helix C-termini and can be grouped into two classes based on the number of residues at the loop end. The type shown in figure is by far the most common. Glycine occurs very often in position 5 in the paperclip presented in figure since a residue at this position must adopt a left-handed helical conformation. Hydrogen bond patterns in "paperclips". The dotted lines indicate hydrogen bonds between donor and acceptor atoms (e.g., in A, the carbonyl oxygen of residue 1 and the amide nitrogen of residue 6).

39 L analisi della frequenza con cui certi residui appaiono in eliche e foglietti e ripiegamenti b ha rivelato che ognuna di queste strutture secondarie e caratterizzata da specifici residui che appaiono piu frequentemente di altri

Alfa elica Φ 57 Ψ 47

ALFA ELICA Alfa elica Φ 57 Ψ 47 3.6 L alfa elica un elica destrorsa Residui per giro: : 3.6 (ogni( ossigeno carbonilico forma un legame-h con il gruppo aminico del quarto residuo successivo) Passo per