Global folding of proteins using a limited number of distance constraints.

A Monte Carlo method is presented which can obtain the correct tertiary fold of a protein given the secondary structure and as few as three interactions between each secondary structure unit. This method was used to fold hemerythrin, flavodoxin, bovine pancreatic trypsin inhibitor and a variable light domain from an immunoglobulin using the known secondary structures of these proteins. Each of the proteins was successfully folded to obtain a structure resembling the initial X-ray structure. Reasonable success was also achieved when using a secondary structure prediction algorithm to assign secondary structure. The r.m.s. deviations between the folded proteins and the crystal structures are in the order of 3-5 A for the backbone coordinates. Evaluation of the r.m.s. deviations between members of the globin family indicates that two equivalent overall folds may have r.m.s. deviations of this or even larger magnitude. The limiting number of constraints necessary to achieve the correct fold is discussed.