EXHAUSTIVE ENUMERATION OF PROTEIN CONFORMATIONS USING EXPERIMENTAL RESTRAINTS

We present an efficient new algorithm that enumerates all possible con formations of a protein that satisfy a given set of distance restraint s. Rapid growth of all possible self-avoiding conformations on the dia mond lattice provides construction of alpha-carbon representations of a protein fold. We investigated the dependence of the number of confor mations on pairwise distance restraints for the proteins crambin, panc reatic trypsin inhibitor, and ubiquitin. Knowledge of between one and two contacts per monomer is shown to be sufficient to restrict the num ber of candidate structures to approximately 1,000 conformations. Pair wise RMS deviations of atomic position comparisons between pairs of th ese 1,000 structures revealed that these conformations can be grouped into about 25 families of structures. These results suggest a new appr oach to assessing alternative protein folds given a very limited numbe r of distance restraints, Such restraints are available from several e xperimental techniques such as NMR, NOESY, energy transfer fluorescenc e spectroscopy, and crosslinking experiments. This work focuses on exh austive enumeration of protein structures with emphasis on the possibl e use of NOESY-determined distance restraints.