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The two most obvious approaches to the problem of predicting protein structure from sequence would be either to simulate the folding process in detail, or to search the entire conformational space available to the polypeptide for the correct fold. The former appears to be beyond our reach. Even the structures of small organic molecules cannot be generated using algorithmic implementations of the `laws of physics' for atomic interactions. Full atom protein folding simulations are completely beyond current computational resources. Short simulations from the folded state, known as molecular dynamics simulations, are possible but do not accurately recreate the behaviour of folded proteins in solution.
Exhaustive conformational search is also out of reach; the number of possible conformations is immense and would take too long to explore either computationally or in vivo during folding[Levinthal, 1968]. In an attempt to reduce the search space, a common approach is to use a simplified polypeptide representation and restrain atom or residue positions to a lattice[Dill et al., 1995]. Folding or conformational search experiments are rarely successful, even for small proteins. Theoretical experiments using these algorithms may be informative however. For example, Thomas and Dillthomas:jmb96 showed using hypothetical two dimensional lattice simulations that statistical potentials (like those used in threading) do not accurately portray the true interaction energies in protein folding; they exhibit distance dependencies which are the indirect consequence of hydrophobic burial in the core (see Section 1.4.2).