Abstract
A broad range of computational methods exist for the estimation of ligand–protein binding affinities. In this chapter we will provide a guide to the linear interaction energy (LIE) method for binding free energy calculations, focusing on the drug design problem. The method is implemented in combination with molecular dynamics (MD) sampling of relevant conformations of the ligands and complexes under consideration. The detailed procedure for MD sampling is followed by key notes in order to properly analyze such sampling and obtain sufficiently accurate estimations of ligand-binding affinities.
Key words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Åqvist, J., Medina, C., and Samuelsson, J. E. (1994) A new method for predicting binding affinity in computer-aided drug design. Protein Eng 7, 385–391.
Åqvist, J., and Marelius, J. (2001) The linear interaction energy method for predicting ligand binding free energies. Comb Chem High Throughput Screen 4, 613–626.
Bjelic, S., Nervall, M., Gutiérrez-de-Terán, H., Ersmark, K., Hallberg, A., and Aqvist, J. (2007) Computational inhibitor design against malaria plasmepsins. Cell Mol Life Sci 64, 2285–2305.
Wang, R., Lai, L., and Wang, S. (2002) Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J Comput-Aided Mol Des 16, 11–26.
Hulten, J., Bonham, N. M., Nillroth, U., Hansson, T., Zuccarello, G., Bouzide, A., Åqvist, J., Classon, B., Danielson, U. H., Karlen, A., Kvarnstrom, I., Samuelsson, B., and Hallberg, A. (1997) Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities. J Med Chem 40, 885–897.
Marelius, J., Graffner-Nordberg, M., Hans-son, T., Hallberg, A., and Åqvist, J. (1998) Computation of affinity and selectivity: bind- ing of 2,4-diaminopteridine and 2,4-diamino-quinazoline inhibitors to dihydrofolate reductases. J Comput-Aided Mol Des 12, 119–131.
Wallin, G., Nervall, M., Carlsson, J., and Aqvist, J. (2009) Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method. J Chem Theor Comput 5, 380–395.
Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004) Development and testing of a general amber force field. J Comput Chem 25, 1157–1174.
Stjernschantz, E., Marelius, J., Medina, C., Jacobsson, M., Vermeulen, N. P. E., and Oostenbrink, C. (2006) Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization? An evaluation of the linear interaction energy (LIE) method. J Chem Inf Model 46, 1972–1983.
Lee, F. S., Chu, Z. T., Bolger, M. B., and Warshel, A. (1992) Calculations of Antibody-Antigen Interactions: Microscopic and Semi-Microscopic Evaluation of the Free Energies of Binding of Phosphorylcholine Analogs to McPC603. Prot. Eng. 5, 215–228.
Marcus, R. A. (1964) Chemical and Electrochemical Electron-Transfer Theory. Ann Rev Phys Chem 15, 155–196.
Almlof, M., Carlsson, J., and Aqvist, J. (2007) Improving the accuracy of the linear interaction energy method for solvation free energies. J Chem Theor Comput 3, 2162–2175.
Åqvist, J., and Hansson, T. (1996) On the Validity of Electrostatic Linear Response in Polar Solvents. J Phys Chem 100, 9512–9521.
Almlof, M., Aqvist, J., Smalas, A. O., and Brandsdal, B. O. (2006) Probing the effect of point mutations at protein-protein interfaces with free energy calculations. Biophys J 90, 433–442.
Nervall, M., Hanspers, P., Carlsson, J., Boukharta, L., and Aqvist, J. (2008) Predicting binding modes from free energy calculations. J Med Chem 51, 2657–2667.
Almlöf, M., Brandsdal, B. O., and Åqvist, J. (2004) Binding Affinity Prediction with Different Force Fields: Examination of the Linear Interaction Energy Method. J Comp Chem 25, 1242–1254.
Osterberg, F., and Åqvist, J. (2005) Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods. FEBS Lett 579, 2939–2939.
Luzhkov, V. B., and Åqvist, J. (2001) Mechanisms of tetraethylammonium ion block in the KcsA potassium channel. FEBS Lett 495, 191–196.
Carlson, H. A., and Jorgensen, W. L. (1995) An Extended Linear-Response Method for Determining Free-Energies of Hydration. J Phys Chem 99, 10667–10673.
Huang, D., and Caflisch, A. (2004) Efficient evaluation of binding free energy using continuum electrostatics solvation. J Med Chem 47, 5791–5797.
Su, Y., Gallicchio, E., Das, K., Arnold, E., and Levy, R. M. (2007) Linear Interaction Energy (LIE) Models for Ligand Binding in Implicit Solvent: Theory and Application to the Binding of NNRTIs to HIV-1 Reverse Transcriptase. J Chem Theor Comput 3, 256–277.
Wang, W., Wang, J., and Kollman, P. A. (1999) What determines the van der Waals coefficient beta in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations? Proteins 34, 395–402.
Gutiérrez-de-Terán, H., Nervall, M., Dunn, B. M., Clemente, J. C., and Aqvist, J. (2006) Computational analysis of plasmepsin IV bound to an allophenylnorstatine inhibitor. FEBS Lett 580, 5910–5916.
Marelius, J., Kolmodin, K., Feierberg, I., and Åqvist, J. (1999) Q: An MD program for free energy calculations and empirical valence bond simulations in biomolecular systems. J Mol Graph Modelling 16, 213–225.
King, G., and Warshel, A. (1989) A Surface Constrained All-Atom Solvent Model for Effective Simulations of Polar Solutions. J Chem Phys 91, 3647–3661.
Lee, F. S., and Warshel, A. (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97, 3100–3107.
Jorgensen, W. L., Maxwell, D. S., and Tirado-Rives, J. (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118, 11225–11236.
Bursavich, M. G., and Rich, D. H. (2002) Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles. J Med Chem 45, 541–558.
Carlsson, J., Ander, M., Nervall, M., and Aqvist, J. (2006) Continuum solvation models in the linear interaction energy method. J Phys Chem B 110, 12034–12041.
Carlsson, J., Boukharta, L., and Aqvist, J. (2008) Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase. J Med Chem 51, 2648–2656.
Hansson, T., Marelius, J., and Åqvist, J. (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comput Aided Mol Des 12, 27–35.
Allen, M. P., and Tildesley, D. J. (1987) Computer Simulation of Liquids. Oxford University Press, Oxford, U.K.
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
Gutiérrez-de-Terán, H., Åqvist, J. (2012). Linear Interaction Energy: Method and Applications in Drug Design. 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_20
Download citation
DOI: https://doi.org/10.1007/978-1-61779-465-0_20
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