Padmanabhan Balaram

The stereochemistry of peptides containing α-aminoisobutyric acid

The introduction of alpha-aminoisobutyric acid (Aib) into peptides dramatically limits the range of accessible backbone conformations. The presence of two geminal methyl groups at C alpha sterically compels Aib residues to largely favor structures in the right- or left-handed 3(10)/alpha-helical regions (phi approximately +/- 60 +/- 20 degrees, psi approximately +/- 30 +/- 20 degrees) of the peptide conformational map. Aib residues occur extensively in microbial peptides which form transmembrane channels. This observation has stimulated considerable interest in the stereochemistry of Aib peptides. This review summarizes theoretical studies on the conformations of Aib residues and examines the available data on solid-state structures, derived from single crystal X-ray diffraction studies. Crystal structures of over three dozen Aib-containing peptides, ranging in length from 2 to 11 residues, have been reported so far which exemplify various types of beta-turns, consecutive beta-turns, and helical structures. Examples of nonhydrogen bonded and cyclic structures are also described. The crystallographic results compare well with structural studies in solution, establishing that Aib peptides can provide rigid structural models for the development of spectroscopic methods of peptide conformational analysis.

Structural chemistry of peptides containing backbone expanded amino acid residues: conformational features of β, γ, and hybrid peptides.

6. ω Amino Acids in Hairpins 672 6.1. Insertion into Turn Segments 672 6.2. Extended Strands 673 7. Conformational Representations 673 7.1. Conformationally Constrained Residues 675 8. Conformational Variability and Biological Activity 677 8.1. Conformational Variability in Solution 677 8.2. Biological Activity of Synthetic Peptides 678 9. Revisiting Hydrogen-Bonded Rings and Polypeptide Helices 678

Non-standard amino acids in peptide design and protein engineering

The introduction of non-coded amino acids with well defined stereochemical and functional properties will greatly enhance the scope of protein design and engineering. The present state of methodologies for incorporation of non-coded residues into proteins is examined. The prospects for conformationally constrained amino acid residues are evaluated in the light of peptide structural studies. Templates for secondary-structure nucleation and recent experiences in the incorporation of novel residues into proteins are considered.

Triosephosphate isomerase from Plasmodium falciparum: the crystal structure provides insights into antimalarial drug design.

BACKGROUND Malaria caused by the parasite Plasmodium falciparum is a major public health concern. The parasite lacks a functional tricarboxylic acid cycle, making glycolysis its sole energy source. Although parasite enzymes have been considered as potential antimalarial drug targets, little is known about their structural biology. Here we report the crystal structure of triosephosphate isomerase (TIM) from P. falciparum at 2.2 A resolution. RESULTS The crystal structure of P. falciparum TIM (PfTIM), expressed in Escherichia coli, was determined by the molecular replacement method using the structure of trypanosomal TIM as the starting model. Comparison of the PfTIM structure with other TIM structures, particularly human TIM, revealed several differences. In most TIMs the residue at position 183 is a glutamate but in PfTIM it is a leucine. This leucine residue is completely exposed and together with the surrounding positively charged patch, may be responsible for binding TIM to the erythrocyte membrane. Another interesting feature is the occurrence of a cysteine residue at the dimer interface of PfTIM (Cys13), in contrast to human TIM where this residue is a methionine. Finally, residue 96 of human TIM (Ser96), which occurs near the active site, has been replaced by phenylalanine in PfTIM. CONCLUSIONS Although the human and Plasmodium enzymes share 42% amino acid sequence identity, several key differences suggest that PfTIM may turn out to be a potential drug target. We have identified a region which may be responsible for binding PfTIM to cytoskeletal elements or the band 3 protein of erythrocytes; attachment to the erythrocyte membrane may subsequently lead to the extracellular exposure of parts of the protein. This feature may be important in view of a recent report that patients suffering from P. falciparum malaria mount an antibody response to TIM leading to prolonged hemolysis. A second approach to drug design may be provided by the mutation of the largely conserved residue (Ser96) to phenylalanine in PfTIM. This difference may be of importance in designing specific active-site inhibitors against the enzyme. Finally, specific inhibition of PfTIM subunit assembly might be possible by targeting Cys13 at the dimer interface. The crystal structure of PfTIM provides a framework for new therapeutic leads.

The crystal and molecular structure of the amino terminal tetrapeptide of alamethicin. A novel 310 helical conformation

The molecular structure of N-benzyloxycarbonyl-α-aminoisobutyryl-prolyl-α-aminoisobutyryl-alanyl methyl ester (Z-Aib-Pro-Aib-Ala-OMe), the amino terminal tetrapeptide of alamethicin is reported. The molecule contains two consecutive β-turns with Aib-Pro and Pro-Aib at the corners, forming an incipient 310 helix. This constitutes the first example of an X2-Pro3 β-turn in the crystal structure of a small peptide.

A C-H...O hydrogen bond stabilized polypeptide chain reversal motif at the C terminus of helices in proteins

The serendipitous observation of a C–H···O, hydrogen bond mediated polypeptide chain reversal in synthetic peptide helices has led to a search for the occurrence of a similar motif in protein structures. From a dataset of 634 proteins, 1304 helices terminating in a Schellman motif have been examined. The C–H···O interaction between the T−4

Gabapentin: a stereochemically constrained gamma amino acid residue in hybrid peptide design.

C^\alpha H

The 310 helical conformation of a pentapeptide containing a-aminoisobutyric acid (Aib): X-ray crystal structure of Tos-(Aib)5 OMe

and T+1 C=O group

Aib residues in peptaibiotics and synthetic sequences: analysis of nonhelical conformations.

(C...O \leq3.5 \AA)

Comparison of helix-stabilizing effects of α,α-dialkyl glycines with linear and cycloalkyl side chains

becomes possible only when the T+1 residue adopts an extended