Solution conformations of structured peptides: continuum electrostatics versus distance-dependent dielectric functions

To compare different implicit solvent potentials, the folding thermodynamic s of the helical peptide RN24 and the beta-hairpin peptide BH8 are studied by molecular dynamics simulation with adaptive umbrella sampling. As the po tential energy functions, the analytical continuum solvent (ACS) potential and three simplified variants, termed EPSR1, EPSR4 and EPSR10. are used. Th e ACS potential is a combination of the standard CHARMM force field for the internal energy (bonds, angles, dihedrals) and the van der Waals energy wi th the analytical continuum electrostatic (ACE) potential and a non-polar s olvation potential. The EPSR potentials differ from the ACS potential by th e use of Coulomb's law with a distance-dependent dielectric function to cal culate the electrostatic energy. With the ACS potential, quantitative agree ment with experiment is obtained for the helix propensity (RN24: 62% calcul ated vs 50-60% experiment) and the P-hairpin propensity (BH8: 33% calculate d vs 19-37% experiment) of the peptides. During the simulations with the EP SR potentials, no significant formation of secondary structure is observed. It is shown that the preference for coil conformations over conformations with secondary structure by the EPSR potentials is due to an overestimation of the energy of salt bridge formation, independent of the magnitude of th e Coulomb energy relative to the other energy terms. Possible improvements of the distance-dependent dielectric functions which may permit their appli cation to the simulation of peptide folding, are discussed.