Barry Robson

This chapter reexamines the problem of protein folding in view of the earlier convenient folding models but in a modern format. With powerful computers, folding simulators today need to get away from explaining their work so much in terms of a long standing energy landscape model, which is incomplete. The amino acid sequence somehow codes for the manifold topologies in a phase space that can be much more complex. Any method that predicts a protein structure is not necessarily a simulated folding, and if it is, it also implies a prediction of the pathway and mechanisms, not just the final state. It the final native structure that remains, for most workers, of paramount interest because of the further scientific and medical implications. While Cell remains to be tested in the protein-folding arena, both BlueGene and Cell may still emerge as potentially significant moments in the history of protein-folding science (or at least in high-performance hardware that enables it).

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Downloaded from rsta.royalsocietypublishing.org on October 9, 2010 334 TLBLUNDELL AND OTHERS is no significant sequence homology, the tertiary structure may still be modelled approximately if a pattern of residue types or a ' fingerprint ' can be identified which is characteristic of a ...

The solution conformations of thyrotrophin-releasing hormone (TRH), a biologically-active tripeptide, have been predicted computationally using a method which represents solution effects as a dielectric continuum surrounding the molecule throughout energy minimisation; this is described as the reaction field contribution. The predicted conformations have been compared with previous experimental and theoretical studies. Favoured conformations of TRH under other simulated conditions have also been examined, including the behaviour of the cis isomer, and have been related to possible interactions with intermediates and with specific receptors. The relevance of these predictions to the design of biologically-active analogues of TRH has been analysed.