College of Liberal Arts & Sciences

Conformationally Constrained Designed Peptides forming Nanotubes and β-hairpins

Monday, March 5, 2012

March 5, Mon 2012
11:00 am, MRB 200 Conference Room

Dr. Upadhyayula Surya Raghavender

SRI International

Conformationally Constrained Designed Peptides forming Nanotubes and β-hairpins


The focus of the research is the crystallographic characterization of designed peptides adopting specific protein secondary structural motifs. In particular, the research aimed at the characterization of β-turns, β-hairpins and peptide nanotubes and modeling of the encapsulated water wires. The serendipitous discovery of the formation of empty channels in a linear, acyclic, hydrophobic pentapeptide led to the experimental characterization of a number of related peptides with sequence modifications at specific positions. Efforts directed to enhance the pore diameter to accommodate solute molecules led to the observation of channels with encapsulated water molecules. The structure of the water molecules in the confined channels was determined by analyzing the geometry and interactions of the encapsulated water molecules, leading to the proposal of “water wires” in the hydrophobic peptide channels. Two different forms of water wires, with differing hydrogen bond lengths (strengths) between the adjacent water molecules, were characterized. The orientation of the water wires encapsulated in peptide channels was derived theoretically by calculating and comparing the energies corresponding to the dipole moments of the peptide channels and the water wires. Antiparallel orientation of the peptide and water wires is preferred over parallel orientation. β-hairpins represent the best system of studying and understanding the formation of β-sheets in proteins. Β-hairpin comprises of two antiparallel β-strands connected by a tight β-turn. Heterochiral diproline segments were used to nucleate the prime β-turns (Type II’) in synthetic designed β-hairpins. Sequence variation across the strand segments led to the crystallographic characterization of β-hairpins with two different kinds of packing arrangements (parallel and orthogonal) in the crystal lattice. Different varieties of polymorphic forms of β-hairpins were characterized. β-hairpins are recalcitrant to crystallization often leading to the forming of aggregates/precipates, and the crystals grown are invariably observed to be plate-shaped. A method of corelating the underlying strong- (regular h-bonds) and weak-interactions (e.g., C-H...O, π...π) observed in the crystal lattice to the externally grown faces of the crystal was proposed, leading to an understanding of the formation of β-sheet structure in crystals. Extensive analysis of conformational preferences of the naturally occurring amino acids and non-natural amino acids, as found incorporated in acyclic peptides in Cambridge Structural Database, was carried out. The study sheds light on the possibility of incorporation of some of these amino acids in specific positions in a polypeptide sequence to achieve a desired target conformation.

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