Computational design of glycopeptides and cyclic peptides.
Rogers, Julia R.
- Protein therapeutics are an exceptionally valuable class of drug that typically exhibit higher target specificity and potency compared to their small molecule counterparts. However, structural instability of protein therapeutics often plagues their pharmaceutical development. Glycosylation has been shown to ameliorate issues of structural instability. To fully utilize the benefits of glycosylation ... read morein protein design, the effects of glycosylation on protein structure, and subsequent activity, need to be understood to such a degree that glycans can be rationally incorporated into non-glycosylated proteins. In this study, we investigate the effects of specific protein-sugar interactions on protein secondary structure with structural bioinformatics. Wet experiments are used to further test predictions from structural bioinformatics. This molecular level knowledge of how sugars mediate protein structure can further our understanding of the intrinsic biophysical properties of glycoproteins and enable glycosylation to be used to engineer stable protein structures.Another modification that can improve the stability of peptide therapeutics is cyclization. However, the rational design of cyclic peptide therapeutics remains underexplored since their structures are difficult to predict de novo. Indeed, cyclic peptide structural dynamics vary greatly compared to that of linear peptides. In comparison to a linear hexapeptide, cyclic hexapeptides have experimentally been shown to adopt structures with two β-turns. With a limited number of conformations, cyclic hexapeptides are ideal models to study how various types of β-turns interchange to produce different cyclic peptide structures. From analysis of molecular dynamics simulations of a highly flexible cyclic hexapeptide, conformational switches were found to occur via coherent two-dihedral changes. These mechanistic insights guided the development of simulation methods to more efficiently sample cyclic peptide structures.read less