Predicting difficult peptide sequences

In order to effectively assembly difficult peptides, more complex protocols aimed at the disruption of secondary structure formation need to be introduced prior to the onset of synthetic difficulties. Ideally, this could be achieved if a predictive method describing where and when -structure formation will occur, based simply on examination of the primary sequence, was available. Unfortunately, there is no complete solution available to date, although a number of groups have developed reasonably successful guidelines. Current predictive methods are derived from four main investigations  

Statistical analysis of data gathered during the SPPS of hundreds of peptides (43-46)  

Ab initio calculations based upon Chou and Fasman parameters (47) from known protein structures (28)  

Correlation of protected peptide solubility in solution with structure (32, 48,49)  

The effects of host-guest substitutions within a given difficult peptide framework (50,51). 

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RC de L Milton, SCF Milton, PA Adams. Prediction of difficult sequences in solid-phase peptide synthesis. J Am Chem Soc 112, 6039, 1990. 

Given the above limitations, however, it is still difficult to predict which sequences will or will not form (3-sheet structures within the context of head-to-tail cyclic (3-sheet scaffolds. Our group has utilized the 14-residue (3-sheet peptide, GSM (2, Scheme 2), as the basis for the studies reported below. GS14 (2) has the sequence c[-VKLKV-d-YPLKVKL-d-YP-] which contains two (3-strands of five residues each, as well as two type II (3-turns. The three-dimensional structure of GS14 (2) determined by NMR is shown in Scheme 2.[16]... 

Interaction of the solute with radicals from the water is the first of a sequence of reactions which finally leads to stable products. Kinetic studies of the type cited give valuable information about the primary radical species and their relative reaction rates with molecules of different types. When sufficient data have been accumulated, it should be possible to predict the course of radiolysis in complex molecules. From the nature and yields of the products and by observing the effects on them of various factors such as concentration, pH, 02, and specific radical scavengers, it is often possible to speculate about the mechanisms by which products are formed. More often than not, this is a difficult problem because the products, even from relatively simple compounds, prove to be complex. Furthermore, it is often possible to produce more than one mechanism to fit the experimental data. The proteins are particularly difficult because of their complex structures. They contain approximately 20 different amino acids with an average of more than three carbon atoms in the side chains, which vary considerably in their structure hence, the possible number of products is large. For this reason, model compounds such as peptides and polyamino acids have been studied because they contain the peptide linkage but are free from the complications which arise from the diversity of the amino acid residues in a protein. A further practical difficulty which applies to chem-... 

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