CONFORMATIONAL DISTRIBUTION OF A TETRAPEPTIDE IN SOLUTION USING A COMBINED RANDOM SEARCH AND CONTINUUM DIELECTRIC APPROACH

The gas-phase and solution energy minima of the tetrapeptide Arg-Cys-G ly-Val were searched in its dihedral angle conformational space. Confo rmations were generated randomly and then energy minimized in vacuum a nd solution (using explicit representation of water molecules). The re lative free energies of the solvated conformations were calculated usi ng the continuum dielectric method. A combination of random search and continuum dielectric methods yields not only the energy minima but al so their probable conformational distribution. No preferred conformati on is predicted for the RCGV peptide in solution. This is due to a fin e balance between the electrostatic free energy, which favors compact conformations with opposite charges close together, and the solvation free energy, which favors extended conformations with well separated c harged groups that can be optimally solvated. Thus, in solution low-en ergy structures are found with opposite charges both close to each oth er and well separated. In vacuum or an organic solvent with low dielec tric constant, compact conformations with opposite charges close to ea ch other are expected. In general, solvation reduces the tendency for opposite charges to come close together and vastly increases the numbe r of favorable conformations.