Amino acids side chain constraints

Protein segments adopt only a finite number of conformations in folded proteins.This limited dictionary of templates may be due to the inherent steric constraints of the backbone and other packing and electrostatic interactions in protein folding. This was most graphically demonstrated by Jones and Thirup. They showed that the majority of the polypeptide backbone of a new structure can be built up from component pieces of other structures, whether or not they are related. Unger et al. showed, in fact, that 76% of the main chain structure of an 82 protein data set can be constructed using only 100 unique hexapeptide templates. Amino acid side chains are also found in a restricted set of conformers. Recent work in our laboratory has shown that a set of four tetrapeptide templates is sufficient to define almost all loop conformations. 

A further investigated group of local constraints are derivatives of the natural amino acids proline. Proline analogs displaying the characteristics of other amino acids are referred to as proline-amino acid chimeras, and have been used to study the spatial requirements for receptor affinity and biological activity of both natural amino acids and peptides. For example, p-substituted-prolines such as 3-carboxyproline, 3-phenylproline, and 3-di-methylproline combine amino acid side chain functionality with proline s conformational... 

The restriction of the conformational flexibility of the peptide backbone can also be achieved by the use of constrained amino acids. Thereby, introduction of a single amino acid as structural constraint, if carefully chosen, may have a dramatic effect on the structure of the whole molecifle. Thus, various constrained amino acids can have direct influences on the shape of the peptide [142]. Methylation or even larger alkylation in the N- or C -position causes steric hindrance in the main chain but also in the side chain, resulting in conformational rigidity and also affects the hydrophobicity [143]. 

In view of these constraints, we recently suggested a different strategy for the improvement of the material properties of synthetic poly (amino acids) (12). Our approach is based on the replacement of the peptide bonds in the backbone of synthetic poly(amino acids) by a variety of "nonamide" Linkages. "Backbone modification," as opposed to "side chain modification," represents a fundamentally different approach that has not yet been explored in detail and that can potentially be used to prepare a whole family of structurally new polymers. 

Steric constraints introduced by the /V-alkyl group. 12,17 The steric hindrance of the /V-alkyl group is experienced both by the peptide backbone and the side chains of neighboring amino acids. 18 ... 

Given these requirements, it is obvious that the P-tetralin based N- and C-caps could not be used as position-independent templates. While the P-tetralin amino acid and the dipeptide units are compatible with a position-independent template design, the biphenyl ether linker unit clearly was not. In N- and C-caps, the linker unit forms a side chain (P-tetralin) to backbone constraint (either to the C-terminal carboxylate or the N-terminal amine), and only one attachment site for a peptide... 

Inspection of our 3-D model of the thrombin receptor suggested that the Glu-347/Ser-42-NH3 interaction is superior to one involving Ser-42-NH3+ and Asp-256 in EC2. This was partly because the disulfide bridge involving Cys-254 created a constraint that anchored Asp-256 away from the junction between EC1 and EC2, and away from the transmembrane interface (Figure 8). With SFLLRN in a turn-type conformation, the Asp-256 side chain was pointed towards the N-terminal extension in the receptor model. This important acidic residue might interact directly with a basic side chain within a segment of the receptor N-terminal peptide. However, since alanine mutations for Lys-76 or Lys-82 yielded receptors with wild-type behavior, these amino acids apparently do not interact with Asp-256. 

Peptoid helices are detected in structure-supporting solvents even in relatively short oligomers. Because intramolecular C=0- H-N H-bond formation cannot be the driving force for peptoid secondary structure, the steric influence of the bulky and chiral side chain is likely to provide the required constraint. Interactions between side-chain groups, and between side chains and the carbonyls of the main-chain amides, may add stability to the ordered secondary structure. However, for very short oligomers (34) or peptoids based on N-substituted a-amino acids with a small side chain (35), such as Nala (also termed sarcosine, Sar, 9), complex mixtures of conformers associated with either cis or trans tertiary amide groups have been detected. In addition to the classic CD technique, the contribution of other spectroscopies, such as pulsed ESR (36), may be of value for the 3-D structural validation of peptoid molecules. 

The a-helix is disrupted by proline residues, in which the ring imposes geometric constraints, and by regions in which numerous amino acid residues have charged groups or large, bulky side chains. 

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