FREE-ENERGIES OF TRANSFER OF TRP ANALOGS FROM CHLOROFORM TO WATER - COMPARISON OF THEORY AND EXPERIMENT AND THE IMPORTANCE OF ADEQUATE TREATMENT OF ELECTROSTATIC AND INTERNAL INTERACTIONS

Experimentally determined water/chloroform partition coefficients for three indole derivatives (3-methylindole, N-acetyltryptamine, and 3-(3 '-indolyl)propionic acid N-methylamide), models of the amino acid tryp tophan, are compared to free-energy differences calculated using molec ular dynamics simulations. The effect of the choice of force field, th e choice of pathway along which the free-energy change is calculated, the inclusion of free-energy contributions from constraints, and the t reatment of long-range interactions on the agreement with the experime ntal data for this system are investigated with an eye to understandin g the importance of the different aspects of the molecular model and c omputational procedure. It is demonstrated that, although the compound s are neutral and do not differ much in dipole moment or charge distri bution, the incorporation of a reaction field to treat long-range elec trostatic interactions is necessary to reproduce the experimentally ob served trends. The implications of these findings for free-energy calc ulations in general and for the estimation of partition coefficients i n particular are discussed.