The last application of the loop analysis work is to the design of novel proteins, using the techniques of protein engineering. Using this knowledge-based approach it should be possible to replace long loops by short loops and viceversa. Sequences of homologous proteins suggest that such mutations will not affect the general fold of the protein. Similarly the sequence templates can be used as templates to design a protein from scratch. For example, a P-hairpin with Gly-Gly, Asx-Gly, Gly-Thr or Gly-Ser for the loop would be a good starting point in the design of a beta-barrel. Several laboratories around the world are attempting such designs (e.g. Richardson and Richardson"), but experimental proof for a successful design has yet to be achieved.
Conclusions
This paper has described some detailed analysis of the structures of loops in proteins. We have shown that even in the 'random coil' regions there are recurring motifs which are found in unrelated proteins and probably reflect structural stability rather than divergent evolution. In this respect they can be compared to the helix or beta strand although of course they are much less freauent. These common structures are u s e h in modelling loops but there is still a major problem in the longer loops, whose conformations are much more variable. These conformations are probably determined not only by the local sequence but also by the protein and aaueous environment. Further studies on the structures of these longer loops are required, although global search techniques combined with energy calculations appear the only possible approach to improving predictions.
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