GENFOLD - A GENETIC ALGORITHM FOR FOLDING PROTEIN STRUCTURES USING NMR RESTRAINTS

We report the development and validation of the program GENFOLD, a gen etic algorithm that calculates protein structures using restraints obt ained from NMR, such as distances derived from nuclear Overhauser effe cts, and dihedral angles derived from coupling constants. The program has been tested on three proteins: the POU domain (a small three-helix DNA-binding protein), bovine pancreatic trypsin inhibitor (BPTI), and the starch-binding domain from Aspergillus niger glucoamylase I, a 10 8-residue beta-sheet protein. Structures were calculated for each prot ein using published NMR restraints. In addition, structures were calcu lated for BPTI using artificial restraints generated from a high-resol ution crystal structure. In all cases the fittest calculated structure s were close to the target structure, and could be refined to structur es indistinguishable from the target structures by means of a low-temp erature simulated annealing refinement. The effectiveness of the progr am is similar to that of distance geometry and simulated annealing met hods, and it is capable of using a very wide range of restraints as in put. It can thus be readily extended to the calculation of structures of large proteins, for which few NOE restraints may be available.