Isoleucine conformational

Kubota S, Easman GD (1975) Beta-conformation of polypeptides of valine, isoleucine, and threonine in solution and solid-state - optical and infrared studies. Biopolymers 14 605-631... 

Amphipathic peptides contain amino acid sequences that allow them to adopt membrane active conformations [219]. Usually amphipathic peptides contain a sequence with both hydrophobic amino acids (e.g., isoleucine, valine) and hydrophilic amino acids (e.g., glutamic acid, aspartic acid). These sequences allow the peptide to interact with lipid bilayer. Depending on the peptide sequence these peptides may form a-helix or j6-sheet conformation [219]. They may also interact with different parts of the bilayer. Importantly, these interactions result in a leaky lipid bilayer and, therefore, these features are quite interesting for drug delivery application. Obviously, many of these peptides are toxic due to their strong membrane interactions. 

Two types of geometric effects have been found in this context. One of these effects is exemplified by isoleucine (16), in which the sec-butyl group adopts a gauche conformation and disorder occurs through interchange of ethyl and methyl groups (57). In this situation the sec-butyl group has pseudo mirror symmetry. 

Fig. Z14. The activation of chymotrypsin via proteolytic cleavage, a) Chymotrypsinogen is transformed into the active forms of chymotrypsin n and a by trypsin and autoproteolysis, b) The N-terminal isoleucine residue Ile6 is particularly important for the activity of chymotrypsin. The positively charge NH2 group of llel6 interacts electrostatically with Aspl94 and stabilizes an active conformation of the catalytic center. After Stryer Biochemistry , with permission.

Biopharmaceuticals based on natural proteins and peptides are often called by the same name as the biologic natural material despite differences in one or more amino-acid residues. For example, insulin, which regulates blood glucose and is used clinically to treat type 1 diabetes and some cases of type 2 diabetes, has several variants that are approved for human use. Insulin contains two polypeptides, A and B chains (Figure 1.2), that are linked together by two disulfide bridges to assume a biologically active conformation. Compared with human insulin, insulin extracted from beef tissue exhibits threonine alanine and isoleucine valine substitutions at posi-... 

From such a background, some kinds of polypeptide blend samples have been studied by solid state NMR.27,72 74 Especially, detailed information for four kinds of blend samples such as poly(L-alanine) (PLA)/poly(L-valine) (PLV), PLA/poly(L-isoleucine) (PLIL), poly(D-alanine) (PDA)/PLV and polyglycine (PG)/PLV blends, have been reported. Here, let us describe some reasons why PLA/PLV, PDA/PLV, PLA/PLIL and PG/PLV blends are interesting systems. PLA and PDA in the solid-state can take the a-helix and (3-sheet forms due to intra- and intermolecular HBs, respectively. PG in the solid-state can take the 3j-helix (PG-II) and (3-sheet (PG-I) forms due to intra- and intermolecular HBs, respectively. However, PLIL and PLV in the solid state can predominantly take the (3-sheet form as the stable conformation. For this reason, it is interesting to know whether an isolated a-helix or 3i-helix form polypeptide surrounded by a major polypeptide in the (3-sheet form can take the helical conformation, or not, due to the balance between intramolecular and intermolecular hydrogen bonds. In addition, we would like to know whether a polypeptide in the (3-sheet form surrounded by a major polypeptide in the a-helix or 3 -helix form can take the (3-sheet form. 

The properties of polypeptides and proteins are determined to a large extent by the chemistry of the side chain groups, which may be summarized briefly as follows. Glycine in a peptide permits a maximum of conformational mobility. The nine relatively nonpolar amino acids-alanine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, and tryptophan-serve as building blocks of characteristic shape. Tyrosine and tryptophan also participate in hydrogen bonding and in aromatic aromatic interactions within proteins. 

Figure 1.11 Ramachandran diagrams illustrating the preferred conformations of the polypeptide chain, (a) The allowed regions and their relationship to different types of secondary structure, (b) The different conformational restrictions for the different amino acids. Note the high conformational freedom for glycine (G) and the restrictions on isoleucine (I) and valine (V).

The concept of control of metabolic activity by allosteric enzymes or the control of enzyme activity by ligand-induced conformational changes arose from the study of metabolic pathways and their regulatory enzymes. A good example is the multi-enzymatic sequence catalysing the conversion of L-threonine to L-isoleucine shown in Fig. 5.32. 

Fig. 5.4 The selected oligopeptide GVEIAVKGAEVAAKVGGVEIAVKAGEVAAKVG (only heavy atoms of the backbone are shown) G glycine, V valine, E glutamic acid, I isoleucine, A alanine, K lysine, (a) The lowest-energy a-helical conformation (two-helical bundle with well pronounced hydrophobic interface) and (b) the metastable P conformation (four-member P barrel) of the amino acid sequence. The sequence is a compromise between the a-helix making pattern and the P making pattern. The two glycines in the center of the sequence are expected to make a turn of the backbone, welcome for both a and P forms...

Scheme 5.15 No Irish type II fragmentation and Yang cyclization of isoleucine derivatives, illustrating the influence of conformational equilibria.

Figure 8 Allowed areas of the steric map for various terminally blocked amino acid residues X.45 In area 0, no conformations are allowed. Conformations in areas 1 to 4 are allowed for X = glycine, in areas 2 to 4 for X = alanine, in areas 3 to 4 for higher straight-chain homologs, whereas only area 4 is allowed for X = valine or isoleucine. The circles marked R and L indicate the locations of the standard right-and left-handed a helices on the steric map.

M. Go and H. A. Scheraga, Biopolymers, 23,1961 (1984). Molecular Theory of the Helix-Coil Transition in Polyamino Acids. V. Explanation of the Different Conformational Behavior of Valine, Isoleucine, and Leucine in Aqueous Solution. 

---