Self-consistently optimized statistical mechanical energy functions for sequence structure alignment.

A quantitative form of the principle of minimal frustration is used to obtain from a database analysis statistical mechanical energy functions and gap parameters for aligning sequences to three-dimensional structures. The analysis that partially takes into account correlations in the energy landscape improves upon the previous approximations of Goldstein et al. (1994, 1995) (Goldstein R, Luthey-Schulten Z, Wolynes P, 1994, Proceedings of the 27th Hawaii International Conference on System Sciences. Los Alamitos, California: IEEE Computer Society Press. pp 306-315; Goldstein R, Luthey-Schulten Z, Wolynes P, 1995, In: Elber R, ed. New developments in theoretical studies of proteins. Singapore: World Scientific). The energy function allows for ordering of alignments based on the compatibility of a sequence to be in a given structure (i.e., lowest energy) and therefore removes the necessity of using percent identity or similarity as scoring parameters. The alignments produced by the energy function on distant homologues with low percent identity (less than 21%) are generally better than those generated with evolutionary information. The lowest energy alignment generated with the energy function for sequences containing prosite signatures but unknown structures is a structure containing the same prosite signature, providing a check on the robustness of the algorithm. Finally, the energy function can make use of known experimental evidence as constraints within the alignment algorithm to aid in finding the correct structural alignment.