A supermolecule study of the effect of hydration on the conformational behaviour of leucine-enkephalin

A theoretical conformational study was performed on leu-enkephalin in its zwitterionic form, both in vacuo and in the presence of a number, n, of up to 13 water molecules saturating its first hydration shell. The intramolecular energy of enkephalin as well as the intermolecular enkephalin-water and water-water interaction energies were computed with the SIBFA procedure (Sum of Interactions Between Fragments Ab initio computed), which uses additive ab initio multipole systematics and analytical formulas grounded on ab initio SCF computations. Energy minimizations were performed with a polyvalent minimizer, Merlin, with which three distinct derivative and three distinct nonderivative minimizers can be activated in a sequential fashion. Eight different candidate conformations of enkephalin were used as starting points. These conformations are either those found in distinct X-ray structures, or those proposed on the basis of theoretical computations by other authors. In the absence of hydration, they converged towards distinct folded energy-minima, the best four ones being separated by an energy gap of 8.7 kcal/mol. In marked contrast, with up to n = 13, the energetical separation between the six best conformers narrowed down to congruent to 4 kcal/mol. They can be characterized by: (a) either a direct or a water-mediated ammonium-carboxylate interaction; b) either a close proximity (as in morphine) or a large separation between the aromatic rings of Tyr and Phe (intercenter separations of congruent to 4.5 A and congruent to 10.5 A, respectively), with each of the four mutual combinations of (a) and (b) being represented.