Abstract
The one-step perturbation approach offers an efficient means to estimate free energy differences. It may be applied to estimate solvation free energies, conformational preferences or relative free energies of binding of series of compounds to a common receptor. Applicability of the method depends on the possibility to define a proper reference state which may in itself be an unphysical molecule. Here, we describe practical considerations and explicit guidelines to define a proper reference state, and to efficiently calculate relative free energies. The strengths and limitations of the method are highlighted and special considerations are noted. The method may be applied using many different simulation programs. Here, analyses are exemplified at the hand of the GROMOS simulation package.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Beveridge, D. L., DiCapua, F. M. (1989) Free energy via molecular simulation: Applications to chemical and biomolecular systems. Ann Rev Biophys Biophys Chem 18, 431–492.
Brandsdal, B. O., Österberg, F., Almlöf, M., Feierberg, I., Luzhkov, V. B., Åqvist, J. (2003) Free energy calculations and ligand binding. Adv Prot Chem 66, 123–158.
Kollman, P. (1993) Free energy calculations: Applications to chemical and biochemical phenomena. Chem Rev 93, 2395–2417.
Zwanzig, R. W. (1954) High-temperature equation of state by a perturbation method. I. Nonpolar gases. J Chem Phys 22, 1420–1426.
Liu, H. Y., Mark, A. E., van Gunsteren, W. F. (1996) Estimating the relative free energy of different molecular states with respect to a single reference state. J Phys Chem 100, 9485–9494.
Oostenbrink, C., van Gunsteren, W. F. (2004) Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation. Proteins 54, 237–246.
Beutler, T. C., Mark, A. E., van Schaik, R. C., Gerber, P. R., van Gunsteren, W. F. (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222, 529–539.
Schäfer, H., van Gunsteren, W. F., Mark, A. E. (1999) Estimating relative free energies from a single ensemble: Hydration free energies. J Comput Chem 20, 1604–1617.
Pitera, J. W., van Gunsteren, W. F. (2001) One-step perturbation methods for solvation free energies of polar solutes. J Phys Chem B 105, 11264–11274.
Oostenbrink, C., van Gunsteren, W. F. (2005) Efficient calculation of many stacking and pairing free energies in DNA from a few molecular dynamics simulations. Chem Eur J 11, 4340–4348.
Hritz, J., Oostenbrink, C. (2009) Efficient free energy calculations for compounds with multiple stable conformations separated by high energy barriers. J Phys Chem B 113, 12711–12720.
Lin, Z., Kornfeld, J., Mächler, M., van Gunsteren, W. F. (2010) Prediction of folding equilibria of differently substituted peptides using one-step perturbation. J Am Chem Soc 132, 7226–7278.
Lin, Z., Liu, H. Y., van Gunsteren, W. F. (2010) Using one-step perturbation to predict the effect of changing force-field parameters on the simulated folding equilibrium of a beta-peptide in solution. J Comput Chem 31, 2419–2427.
Oostenbrink, B. C., Pitera, J. W., Van Lipzig, M. M. H., Meerman, J. H. N., van Gunsteren, W. F. (2000) Simulations of the estrogen receptor ligand-binding domain: Affinity of natural ligands and xenoestrogens. J Med Chem 43, 4594–4605.
Oostenbrink, C., van Gunsteren, W. F. (2003) Single-step perturbations to calculate free energy differences from unphysical reference states: Limits on size, flexibility, and character. J Comput Chem 24, 1730–1739.
Oostenbrink, C., van Gunsteren, W. F. (2005) Free energies of ligand binding for structurally diverse compounds. Proc Nat Acad Sci USA 102, 6750–6754.
Oostenbrink, C. (2009) Efficient free energy calculations on small molecule host-guest systems - a combined linear interaction energy/one-step perturbation approach. J Comput Chem 30, 212–221.
Hritz, J., Läppchen, T., Oostenbrink, C. (2010) Binding affinity calculations for 8-substituted GTP analogs to the bacterial cell-division protein FtsZ. Eur Biophys J 29, 1573–1580.
van Gunsteren, W. F., Billeter, S. R., Eising, A. A., Hünenberger, P. H., Krüger, P., Mark, A. E., Scott, W. R. P., Tironi, I. G. (1996) Biomolecular simulation: The GROMOS96 manual and user guide, Vdf Hochschulverlag AG an der ETH Zürich, Zürich.
Christen, M., Hünenberger, P. H., Bakowies, D., Baron, R., Bürgi, R., Geerke, D., Heinz, T. N., Kastenholz, M. A., Kräutler, V., Oostenbrink, C., Peter, C., Trzesniak, D., van Gunsteren, W. F. (2005) The GROMOS software for biomolecular simulation: GROMOS05. J Comput Chem 26, 1719–1751.
Hritz, J., Oostenbrink, C. (2008) Hamiltonian replica exchange molecular dynamics using soft-core interactions. J Chem Phys 128, 144121.
Torrie, G. M., Valleau, J. P. (1977) Nonphysical sampling distibutions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 23, 187–199.
Severance, D. L., Essex, J. W., Jorgensen, W. L. (1995) Generalized alteration of structure and parameters: A new method for free-energy perturbations in systems containing flexible degrees of freedom. J Comput Chem 16, 311–327.
Ryckaert, J.-P., Ciccotti, G., Berendsen, H. J. C. (1977) Numerical integration of cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J Comput Phys 23, 327–341.
Oostenbrink, C., van Lipzig, M. M. H., van Gunsteren, W. F. (2007) Applications of molecular dynamics simulations in drug design, in Comprehensive Medicinal Chemistry II - Vol 4: Computer-Assisted Drug Design (Taylor, J. B., and Triggle, D. J., Eds.) pp 651–668, Elsevier, Amsterdam.
Allen, M. P., Tildesley, D. J. (1987) Computer simulation of liquids, Clarendon press, Oxford.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Oostenbrink, C. (2012). Free Energy Calculations from One-Step Perturbations. In: Baron, R. (eds) Computational Drug Discovery and Design. Methods in Molecular Biology, vol 819. Springer, New York, NY. https://doi.org/10.1007/978-1-61779-465-0_28
Download citation
DOI: https://doi.org/10.1007/978-1-61779-465-0_28
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-61779-464-3
Online ISBN: 978-1-61779-465-0
eBook Packages: Springer Protocols