Peptidic Hydrogels - In-Situ Gelling Polymers: For Biomedical Applications - page 130

down view of the helix. Each turn of an ʱ -helix is 3.6 amino acid residues. The
ʱ -helical structure is held together by hydrogen bonds between backbone CO and
NH functionalities along the helix, holding the helix together tightly, and creat-
ing a fairly rigid secondary structure [ 13 , 36 ]. A common helix design for gelation
involves helices that are composed of amino acid heptads labeled abcdefg , where
the first and fourth amino acids are typically hydrophobic while the remaining
amino acids are polar [ 10 , 13 , 34 ]. This design places the hydrophobic residues
alternatingly 3 or 4 residues apart along the chain, giving the helix a hydropho-
bic face that winds around the surface of the helix. The exposed hydrophobic face
after helix formation is one of the driving forces for higher order structure forma-
tion and gelation. This driving force is discussed further in the quaternary structure
section, as helices collapse into what are called coiled-coils and, ultimately, into
fibrils and hydrogels (cf. Figs. 3 b and 4 ) [ 13 , 34 ]. Certain amino acids are more
likely to be found in ʱ -helices such as lysine, glutamine, glutamic acid, or alanine
[ 1 , 44 ]. ʱ -Helices can be left or right-handed [ 36 ] and can be modified with addi-
tional functional groups [ 1 ]. For example, the Woolfson group uses peptide cus-
tomization to functionalize ʱ -helices with “sticky ends” designed to link helices
together to propagate longer fibrils upon self-assembly [ 1 , 10 , 12 , 13 ].
The other dominant secondary structure is the ʲ -strand that can further hydro-
gen bond together to form ʲ -sheets. Strictly speaking, the strand is the intramo-
lecular secondary structure while interstrand sheet formation is a quaternary
structure. ʲ -Sheets have a distance of 4.7 angstroms between each neighboring
strand, since hydrogen bonds form laterally between the CO and NH functional-
ities of opposite ʲ -strand backbones, as shown schematically in Fig. 3 a. Just as
there are certain amino acids primarily associated with ʱ -helices, hydrophobic and
aromatic amino acids such as phenylalanine, valine, and isoleucine are associated
with the formation of ʲ -sheets [ 13 , 36 , 44 , 83 ]. The presence of hydrophobic resi-
dues in a ʲ -sheet can create hydrophobic faces that build up as ʲ -sheet formation
occurs, causing the ʲ -sheet fibrils to collapse forming hierarchical fibrillar and
fiber nanostructures, further examined later in quaternary structures [ 28 ].
Another variation of the ʲ -sheet is the ʲ -hairpin formed by two ʲ -strands held
together by short amino acid sequence known as a ʲ -turn. The Schneider and
Pochan groups created the family of MAX ʲ -hairpin structures that intramolecu-
larly fold and intermolecularly assemble into nanofibrils with a hydrophobic core.
Figure 5 shows an example of the ʲ -hairpin structure from the group's flagship
MAX1 peptide sequence that collapses to protect hydrophobic valines when trig-
gered [ 28 , 49 ]. The hairpin collapse throughout the solution creates a bilayer fibril,
where hydrogen bonds between carboxyl and amine groups of opposing amino
acid backbones stabilize the parallel structures (dotted lines in the Fig. 5 [ 28 , 49 ]).
Figure 6 shows AFM images of two very similar primary sequences that appear
similar after quaternary structure formation and gelation, but one forms ʱ -helices
while the other forms ʲ -sheets [ 44 ]. Beyond the most common ʱ -helices and
ʲ -sheets, there are other secondary structures that are less observed in peptide
hydrogels [ 19 , 34 , 36 ]. One example is the polyproline helix seen in Fig. 3 c, a
common secondary structure observed in collagen materials and hydrogels [ 84 ].