Design of Short Linear Peptides That Show Hydrogen Bonding Constraints in Water

摘要

Short linear peptides with 4 to 10 residues are considered flexiblenmolecules with entropic limitations on achieving unique conformationsnin water.1 Predominant conformation in these peptides cannbe achieved in water by incorporating amino acids that restrictnaccess to conformational space, such as proline2 and aminoisobutyricnacid (Aib)3 or by using noncovalent interactions,4 such asnπ-stacking. In the water environment, however, hydrogen bondsnare generally not considered to be the major driving force for foldingnand constraining short linear peptides into a distinct conformation.5nWe explored the possibility of designing linear tetrapeptides thatncan fold into a compact secondary structure through intramolecularnhydrogen bonds in the water environment. We began the designnby choosing ST6 and Asx turns7 as the structural motifs to modelnshort linear peptides. In ST turns, side chain oxygen atoms of serinenor threonine form a hydrogen bond with the backbone NH groupsnof the i+2 residues to create a 9-membered ring. The Asx turn isncharacterized by a similar hydrogen bonding pattern of Asp or Asnnto create a 10-membered ring which can be further supported bynan adjacent 7-membered ring as is the case in the N-glycosylationnsequence (NXS/T) in proteins (Figure 1). These motifs provide anbasis for modeling short linear peptides that can adopt a well-definednturn in water through side chain-main chain hydrogen bonds.