Global fold determination from a small number of distance restraints

We have designed a distance geometry-based method for obtaining the tertiary fold of a protein from a limited number of structure-specific distance restraints and the secondary structure assignment. Interresidue distances were predicted from patterns of conserved hydrophobic amino acids deduced from multiple alignments. A simple model chain representing the protein was then folded by projecting its distance matrix into Euclidean spaces with gradually decreasing dimensionality until a final three-dimensional embedding was achieved. Tangled conformations produced by the projection steps were eliminated using a novel filtering algorithm. Information on various aspects of protein structure such as accessibility and chirality was incorporated into the conformation refinement, increasing the robustness of the algorithm. The method successfully identified the correct folds of three small proteins from a small number of restraints, indicating that it could serve as a useful computational tool in protein structure determination from NMR data.