CALCULATION OF CONFORMATIONAL ENSEMBLES FROM POTENTIALS OF MEAN FORCE - AN APPROACH TO THE KNOWLEDGE-BASED PREDICTION OF LOCAL STRUCTURES IN GLOBULAR-PROTEINS

We present a prototype of a new approach to the folding problem of polypeptide chains. This apprach is based on the analysis of known protein structures. It derives the energy potentials for the atomic interactions of all amino acid residue pairs as a function of the distance between the involved atoms. These potentials are then used to calculate the energies of all conformations that exist in the data base with respect to a given sequence. Then, by using only the most stable conformations, clusters of the most probable conformations for the given sequence are obtained. To discuss the results properly we introduce a new classification of segments based on their conformational stability. Special care is taken to allow for sparse data sets. The use of the method is demonstrated in the discussion of the identical oligopeptide sequences found in different conformations in unrelated proteins. VNTFV, for example, adopts a β-strand in ribonuclease but it is found in an α-helical conformation in erythrocruorin. In the case of VNTFV the ensemble obtained consists of a single cluster of β-strand conformations, indicating that this may be the preferred conformation for the pentapeptide. When the flanking residues are included in the calculation the hepapeptide P-VNTFV-H (ribonuclease) again yields an ensemble of β-strands. However, in the ensemble of D-VNTFV-A (erythrocruorin) the major cluster is of α-helical type. In the present study we concentrate on the local aspects of protein conformations. However, the theory presented is quite general and not restricted to oligopeptides. We indicate extentions of the approach to the calculation of global conformations of proteins as well as conceivable applications to a number of molecular systems. © 1990 Academic Press Limited.