Backbone flexibility and stability of reverse turn conformation in a model system.

Molecular dynamics simulations have been used to study differences in propensity to form a disulfide-bridged turn conformation by peptides with sequence Ac-Cys-Pro-Xaa-Cys-NMe. The calculations were limited to three peptides, with Xaa = Aib, Gly and Val. The experimental differences in propensity (in terms of free energy differences delta delta G degree) were reproduced within 2 kJ/mol. The use of a reduced 1-4 non-bonded interaction potential was tested in this system, but was found to give slightly worse agreement with experiment. The stability of alternate conformations was determined systematically. Type I and II turn conformations of the Aib compound have similar free energy; the Val compound is most stable in a type I turn conformation (by 8 kJ/mol), while the Gly compound is most stable in a type II turn conformation (by 5 kJ/mol). Different backbone conformations were obtained for the valine compound in simulations in solution and in the crystal. It is concluded that turn conformations with psi i+2 near 0, as typically seen in proteins, are stabilized by intramolecular hydrogen bonding in the confined environment. However, when exposed to solvent, hydrogen bonds with water stabilize conformations with larger or smaller values of psi i+2 that are more similar to free energy minima in the isolated, terminally blocked, residue.