Global minimization of an off-lattice potential energy function using a chaperone-based refolding method.
A global energy minimization method based on what is known about the mechanisms of the GroEL/GroES chaperonin system is applied to two 22-mers of an off-lattice protein model whose native states are beta-hairpins and which have structural similarity to short peptides known to interact strongly with the GroEL substrate binding domain. These model substrates have been used by other workers to test the effectiveness of a number of global minimization techniques, and are regarded as providing a significant challenge. The minimization method developed here is progressively elaborated from an initial simple form that targets exposed hydrophobic regions for unfolding to include a refolding phase that encourages the later recompactification of partly unfolded substrate; this refolding phase is seen to be crucial in the successful application of the method. The optimal handling of hydrophilic monomers within the model is also systematically explored, and it is seen that the best interpretation of their role is one that allows the chaperonin model to operate in "proofreading" mode whereby misfolded substrates are recognized by their surface exposure of a large proportion of hydrophobic monomers. The final version of the model allows native-like structures to be found quickly, on average for the two 22-mer substrates after 6 or 7 chaperone contacts. These results compare very favorably with those that have been obtained elsewhere using generic global minimization methods such as those based on thermal annealing. The paper concludes with a discussion of the place of the technique within the general category of hypersurface deformation methods for global minimization, and with suggestions as to how the chaperone-based method developed here could be elaborated so as to be effective on longer substrate chains that give rise to more complex tertiary structures in their native states.