Peptides/polypeptides folding

While the a-helix of L-a-peptides and the (M)-3i4 helix of the corresponding peptides have opposite polarity and helicity (see Section 2.2.3.1), the inserhon of two CH2 groups in the backbone of L-a-amino acids leave these two hehx parameters unchanged, both the a-helix and the 2.614-hehx of the resulting y" -peptides being right-handed and polarized from N to C terminus. In view of these similarities, the y-peptide hehcal fold might prove useful as a template to elaborate functional mimetics of bioachve a-polypeptides. 

This chapter aims to summarize our efforts to investigate the effects of fluorinated amino acid substitutes on the interactions with natural protein environments. In addition to a rather specific example concerning the interactions of small peptides with a proteolytic enzyme, we present a simple polypeptide model that aids for a systematic investigation of the interaction pattern of amino acids that differ in side chain length as well as fluorine content within both a hydrophobic and hydrophilic protein environment. Amino acid side chain fluoiination highly affects polypeptide folding due to steric effects, polarization, and fluorous interactions. 

A puzzling problem was posed by Levinthal many years ago.329 We usually assume that the peptide chain folds into one of the most stable conformations possible. However, proteins fold very rapidly. Even today, no computer would be able, in our lifetime, to find by systematic examination the thermodynamically most stable conformation.328 It would likewise be impossible for a folding protein to "try out" more than a tiny fraction of all possible conformations. Yet folded and unfolded proteins often appear to be in a thermodynamic equilibrium Experimental results indicate that denatured proteins are frequently in equilibrium with a compact denatured state or "molten globule" in which hydrophobic groups have become clustered and some secondary structures exists.330-336 From this state the polypeptide may rearrange more slowly through other folding intermediates to the final "native conformation."3363 3361 ... 

Additional polypeptide sequences are necessary for proper peptide chain folding (e.g., C peptide of insulin). 

Like a-polypeptides, 8-polypeptides fold into relatively stable helical and pleated sheet conformations, causing scientists to wonder whether biological activity might be possible with such peptides. Recently, a 8-peptide with biological activity has been synthesized—one that mimics the activity of the hor-... 

Each cimino acid has an eimine (NH2) group, a central carbon atom known as the alpha carbon, a side chain (denoted R), and a carboxylic acid (COOH) group. The amine groups and carboxylic acid groups of amino acids cem be joined in a chain to form polymers of amino acids, known as peptides. Two amino acids form a dipeptide, three form a tripeptide, and chains of four or more amino acids are commonly referred to as polypeptides. Long polypeptides fold into specific conformations, which is what makes up a protein. 

Another feature of peptide structure must be considered. The overall structure of a long polypeptide is determined by its amino acid sequence (primary structure) and whether it forms an a-helix or a P-pleated sheet (secondary structure). It is also possible to fold or coil the peptide chain into a complex, globular structure that is known as its tertiary structure. This is illustrated by the ribbon diagram for ribonuclease A, 131. The peptide chain folds and coils into a very complex structure in 131. This is the tertiary structure of the peptide. 

Baltzer et al. reported a 42 amino acid containing polypeptide folding into a helix-loop-helix motif in solution, which dimerized in an antiparallel mode to form four-helix bundles. NMR and CD spectroscopy was used to study the structural features of the designed polypeptides. On the basis of this helix-loop-helix motif, a histidine containing peptide KO-42 122 (Figure 45a) was synthesized. On the surface of the folded motif, there are six histidines with assigned p a values in the range of 52-1.2. KO-42 shows catalytic efficiency in acyl-transfer and amidation reactions with /7-nitrophenylesters as substrates. The reactivity of histidine is due to its imidazoyl side chain that... 

Most reactions in cells are carried out by enzymes [1], In many instances the rates of enzyme-catalysed reactions are enhanced by a factor of a million. A significantly large fraction of all known enzymes are proteins which are made from twenty naturally occurring amino acids. The amino acids are linked by peptide bonds to fonn polypeptide chains. The primary sequence of a protein specifies the linear order in which the amino acids are linked. To carry out the catalytic activity the linear sequence has to fold to a well defined tliree-dimensional (3D) stmcture. In cells only a relatively small fraction of proteins require assistance from chaperones (helper proteins) [2]. Even in the complicated cellular environment most proteins fold spontaneously upon synthesis. The detennination of the 3D folded stmcture from the one-dimensional primary sequence is the most popular protein folding problem. 

Figure 14.2 Models of a collagen-like peptide with a mutation Gly to Ala in the middle of the peptide (orange). Each polypeptide chain is folded into a polyproline type II helix and three chains form a superhelix similar to part of the collagen molecule. The alanine side chain is accommodated inside the superhelix causing a slight change in the twist of the individual chains, (a) Space-filling model, (b) Ribbon diagram. Compare with Figure 14.1c for the change caused by the alanine substitution. (Adapted from J. Bella et al.. Science 266 75-81, 1994.)...

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