A procedure has been developed for global energy minimization of surface loops of proteins in the presence of a fixed core. The ECEPP potential function has been modified to allow more accurate representations of hydrogen bond interactions and intrinsic torsional energies. A computationally efficient representation of hydration free energy has been introduced. A local minimization procedure has been developed that uses a cutoff distance, minimization with respect to subsets of degrees of freedom, analytical second derivatives, and distance constraints between rigid segments to achieve efficiency in applications to surface loops. Efficient procedures have been developed for deforming segments of the initial backbone structure and for removing overlaps. Global energy minimization of a surface loop is accomplished by generating a sequence (or a trajectory) of local minima, the component steps of which are generated by searching collections of local minima obtained by deforming seven‐residue segments of the surface loop. The search at each component step consists of the following calculations: (1) A large collection of backbone structures is generated by deforming a seven‐residue segment of the initial backbone structure. (2) A collection of low‐energy backbone structures is generated by applying local energy minimization to the resulting collection of backbone structures (interactions involving side chains that will be searched in this component step are not included in the energy). (3) One low‐energy side‐chain structure is generated for each of the resulting low‐energy backbone structures. (4) A collection of low‐energy local minima is generated by applying local energy minimization to the resulting collection of structures. (5) The local minimum with the lowest energy is retained as the next point of the trajectory. Applications of our global search procedure to surface segments of bovine pancreatic trypsin inhibitor (BPTI) and bovine trypsin suggest that component‐step searches are reasonably complete. The computational efficiency of component‐step searches is such that trajectories consisting of about 10 component steps are feasible using an FPS‐5200 array processor. Our procedure for global energy minimization of surface loops is being used to identify and correct problems with the potential function and to calculate protein structure using a combination of sequence homology and global energy minimization. Copyright © 1990 John Wiley & Sons, Inc.
