Estimating relative free energies from a single ensemble: Hydration free energies

• Published in: Journal of computational chemistry Vol. 20; no. 15; pp. 1604 - 1617
• Main Authors: Schäfer, Heiko, Van Gunsteren, Wilfred F., Mark, Alan E.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 30.11.1999
• Subjects: hydration free energies; relative free energies; single ensemble; solvation
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/(SICI)1096-987X(19991130)20:15<1604::AID-JCC2>3.0.CO;2-A

The ability to determine the free energy of solvation for a number of small organic molecules with varying sizes and properties from the coordinate trajectory of a single simulation of a given reference state was investigated. The relative free energies were estimated from a single step perturbation using the perturbation formula. The reference state consisted of a cavity surrounded by solvent. To enhance sampling a soft‐core interaction was used for the cavity. The effect of the size of the cavity, the effective core height, and the length of simulation on the ability to reproduce results obtained from thermodynamic integration calculations was considered. The results using a single step perturbation from an appropriately chosen initial state were comparable to results from thermodynamic integration calculations for a wide range of compounds. Using a large number of compounds the computational efficiency was potentially increased by 2–3 orders of magnitude over traditional free energy approaches. Factors determining the efficiency of the approach are discussed. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1604–1617, 1999