Prediction of the native conformation of a polypeptide by a statistical-mechanical procedure. III. Probable and average conformations of enkephalin.

Abstract

AbstractThe program SMAPPS (Statistical‐Mechanical Algorithm for Predicting Protein Structure) was originally designed to determine the probable and average backbone (ϕ, ψ) conformations of a polypeptide by the application of equilibrium statistical mechanics in conjunction with an adaptive importance sampling Monte Carlo procedure. In the present paper, the algorithm has been extended to include the variation of all side‐chain (χ) and peptide‐bond (ω) dihedral angles of a polypeptide during the Monte Carlo search of the conformational space. To test the effectiveness of the generalized algorithm, SMAPPS was used to calculate the probable and average conformations of Met‐enkephalin for which all dihedral angles of the pentapeptide were allowed to vary. The total conformational energy for each randomly generated structure of Met‐enkephalin was obtained by summing over the interaction energies of all pairs of nonbonded atoms of the whole molecule. The interaction energies were computed by the program ECEPP /2 (Empirical Conformational Energy Program for Peptides). Solvent effects were not included in the computation. The results of the Monte Carlo calculation of the structure of Met‐enkephalin indicate that the thermodynamically preferred conformation of the pentapeptide contains a γ‐turn involving the three residues Gly2‐Gly3‐Phe4. The γ‐turn conformation, however, does not correspond to the structure of lowest conformational energy. Rather, the global minimum‐energy conformation, recently determined by a new optimization technique developed in this laboratory, contains a type II′ β‐bend that is formed by the interaction of the four residues Gly2‐Gly3‐Phe4‐Met5. A similar minimum‐energy conformation is found by the SMAPPS procedure. The thermodynamically preferred γ‐turn structure has a conformational energy of 4.93 kcal/mole higher than the β‐bend structure of lowest energy but, because of the inclusion of entropy in the SMAPPS procedure, it is estimated to be ∼ 9 kcal/mole lower in free energy. The calculation of the average conformation of Met‐enkephalin was repeated until a total of ten independent average conformations were established. As far as the phenylalanine residue of the pentapeptide is concerned, the results of the ten independent average conformations were all found to lie in the region of conformational space corresponding to the γ‐turn. These results further support the conclusion that the γturn conformation is thermodynamically favored.