Global folding of proteins using a limited number of distance constraints

A Monte Carlo method is presented which can obtain the correcttertiary fold of a protein given the secondary structure andas few as three interactions between each secondary structureunit. This method was used to fold hemerythrin, Qavodoxin, bovinepancreatic trypsin inhibitor and a variable light domain froman immunoglobulin using the known secondary structures of theseproteins. Each of the proteins was successfully folded to obtaina structure resembling the initial X-ray structure. Reasonablesuccess was also achieved when using a secondary structure predictionalgorithm to assign secondary structure. The r.m.s. deviationsbetween the folded proteins and the crystal structures are inthe order of 3–5 A for the backbone coordinates. Evaluationof the r.m.s. deviations between members of the globin familyindicates that two equivalent overall folds may have r.m.s.deviations of this or even larger magnitude. The limiting numberof constraints necesssary to achieve the correct fold is discussed.