Determinants of the polyproline II helix from modeling studies.
Despite the fact that Tiffany and Krimm (1968a,b) formulated their hypothesis more than thirty years ago, it is only now that we are beginning to truly appreciate the importance of the PPII helical conformation. Recent experimental work has demonstrated that the polypeptide backbone possesses a significant propensity to adopt the PPII helical conformation (Kelly et al., 2001; Rucker and Creamer, 2002; Shi et al., 2002). The major determinant of this backbone propensity would appear to be backbone solvation, as was originally hinted at by Krimm and Tiffany (1974) and later suggested by a number of groups (Adzhubei and Sternberg, 1993; Sreerama and Woody, 1999; Kelly et al., 2001; Rucker and Creamer, 2002; Shi et al., 2002). The calculations and modeling described above provide data in support of this hypothesis. Each residue has its own propensity to adopt the PPII conformation, with the backbone propensity being modulated by the side chain (Kelly et al., 2001). Short, bulky side chains occlude backbone from solvent and thus disfavor the PPII conformation, while the lack of a side chain or long, flexible side chains tend to favor the conformation (Kelly et al., 2001). Again, the described calculations support this. Steric interactions (Pappu et al., 2000) and side chain conformational entropy alos contribute to the observed propensities. Furthermore, as suggested from surveys of PPII helices in proteins of known structure (Stapley and Creamer, 1999), side chain-to-backbone hydrogen bonds may well play a role in stabilizing PPII helices. The survey data, plus supporting calculations, also suggest that some polar residues may play a PPII helic-capping role analogous to that observed in alpha-helices (Presta and Rose, 1988; Aurora and Rose, 1998). Taken in sum, an atomic-level picture of the stabilization of PPII helices is beginning to emerge. Once the determinants of PPII helix formation are known in more detail, it will become possible to apply them, along with the known determinants of the alpha-helical conformation, to the understanding of protein unfolded states. If, as suggested at the beginning of this article, protein unfolded states are dominated by residues in the PPII and alpha-conformations, these data will allow for modeling of the unfolded state ensembles of specific proteins with a level of realism that has not been previously anticipated.
Creamer
Trevor P
TP
Center for Structural Biology, Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
Campbell
Margaret N
MN
D006860:Hydrogen Bonding; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*
D010455:Peptides; D011506:Proteins; C011083:polyproline