Free energy perturbation force fields

The problems that occur when one tries to estimate affinity in terms of component terms do not arise when perturbation methods are used with simulations in order to compute potentials of mean force or free energies for molecular transformations simulations use a simple physical force field and thereby implicitly include all component terms discussed earlier. We have used the molecular transformation approach to compute binding affinities from these first principles [14]. The basic approach had been introduced in early work, in which we studied the affinity of xenon for myoglobin [11]. The procedure was to gradually decrease the interactions between xenon atom and protein, and compute the free energy change by standard perturbation methods, cf. (10). An (issential component is to impose a restraint on the... 

Table 7 compares free energies of hydration125 produced by the two types of solvent models that have been presented discrete molecular and continuum. The discrete molecular involved classical force field molecular dynamics (MD) and a free energy perturbation (FEP) technique whereby the solute molecule is annihilated to dummy atoms, so that absolute AGhydration are obtained the continuum were SCRF/PCM calculations, with Claverie-Pierotti Gcavilatlon and Floris-Tomasi Gvdw. The... 

To finalize the development of the aqueous CO2 force field parameters, the C02 model was used in free energy perturbation Monte Carlo (FEP/MC) simulations to determine the solubility of C02 in water. The solubility of C02 in water is calculated as a function of temperature in the development process to maintain transferability of the C02 model to different simulation techniques and to quantify the robustness of the technique used in the solubility calculations. It is also noted that the calculated solubility is based upon the change in the Gibbs energy of the system and that parameter development must account for the entropy/enthalpy balance that contributes to the overall structure of the solute and solvent over the temperature range being modeled [17]. 

Tel. 617-495-4018, fax 617-495-1792, e-mail karplus huchel.bitnet Molecular dynamics package using Chemistry at Harvard Macromolecular Mechanics force field. Extensive scripting language for molecular mechanics, simulations, solvation, electrostatics, crystal packing, vibrational analysis, free energy perturbation (FEP) calculations, quantum mechanics/molecular mechanics calculations, stochastic dynamics, and graphing data. 

Free energy perturbation (FEP) (Lybrand, Ghosh et al., 1985 Mezei and Beveridge, 1986 Jorgensen, 1989) and potential of mean force (PMF) (van Eerden, Briels et al, 1989 Elber, 1990) calculations within molecular mechanical (MM) force fields have proven to be very powerful computational methodologies. These techniques, which have been developed and refined over the last two decades, allow access to important thermodynamic quantities, such as the relative binding free energies of ions within an ionophore(Marrone and Merz, 1992), or inhibitors to an enzyme (Merz and Kollman, 1989). While other techniques, such as linear response theory (Aqvist, Carmen et al.,... 

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