An approach to the multiple-minima problem in protein folding by relaxing dimensionality: Tests on enkephalin

Abstract

An algorithm for locating the region in conformational space containing the global energy minimum of a polypeptide is described. Distances are used as the primary variables in the minimization of an objective function that incorporates both energetic and distancegeometric terms. The latter are obtained from geometry and energy functions, rather than nuclear magnetic resonance experiments, although the algorithm can incorporate distances from nuclear magnetic resonance data if desired. The polypeptide is generated originally in a space of high dimensionality. This has two important consequences. First, all interatomic distances are initially at their energetically most favorable values; i.e. the polypeptide is initially at a global minimum-energy conformation, albeit a high-dimensional one. Second, the relaxation of dimensionality constraints in the early stages of the minimization removes many potential energy barriers that exist in three dimensions, thereby allowing a means of escaping from three-dimensional local minima. These features are used in an algorithm that produces short trajectories of three-dimensional minimum-energy conformations. A conformation in the trajectory is generated by allowing the previous conformation in the trajectory to evolve in a high-dimensional space before returning to three dimensions. The resulting three-dimensional structure is taken to be the next conformation in the trajectory, and the process is iterated. This sequence of conformations results in a limited but efficient sampling of conformational space. Results for test calculations on Met-enkephalin, a pentapeptide with the amino acid sequence H-Tyr-Gly-Gly-Phe-Met-OH, are presented. A tight cluster of conformations (in three-dimensional space) is found with ECEPP energies (Empirical Conformational Energy Program for Peptides) lower than any previously reported. This cluster of conformations defines a region in conformational space in which the global-minimum-energy conformation of enkephalin appears to lie.