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Absolute Alchemical Free Energy Calculations for Ligand Binding: A Beginner’s Guide

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Computational Drug Discovery and Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1762))

Abstract

Many thermodynamic quantities can be extracted from computer simulations that generate an ensemble of microstates according to the principles of statistical mechanics. Among these quantities is the free energy of binding of a small molecule to a macromolecule, such as a protein. Here, we present an introductory overview of a protocol that allows for the estimation of ligand binding free energies via molecular dynamics simulations. While we focus on the binding of organic molecules to proteins, the approach is in principle transferable to any pair of molecules.

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Acknowledgments

The EPSRC and Evotec via the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) support M.A. J.B. is supported by the EPSRC/MRC via the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GSK. We thank David Mobley (University of California, Irvine), John Chodera (MSKCC), and Michael Shirts (University of Colorado, Boulder) for sharing their extensive experience on alchemical free energy calculations through publicly available platforms and personal communications. Work in PCB’s laboratory is currently supported by the MRC, BBSRC, and the John Fell Fund. We thank the Advanced Research Computing (ARC) facility, the EPSRC UK National Service for Computational Chemistry Software (NSCCS) at Imperial College London (grant no. EP/J003921/1), and the ARCHER UK National Supercomputing Services for computer time granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://www.hecbiosim.ac.uk), supported by EPSRC (grant no. EP/L000253/1).

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  1. Matteo Aldeghi

    Present address: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Authors and Affiliations

  1. Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of Oxford, Oxford, UK

    Matteo Aldeghi, Joseph P. Bluck & Philip C. Biggin

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  1. Matteo Aldeghi
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  2. Joseph P. Bluck
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  3. Philip C. Biggin
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Correspondence to Philip C. Biggin .

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Editors and Affiliations

  1. Department of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, KA, India

    Mohini Gore

  2. Department of Biotechnology, Shivaji University, Kolhapur, MH, India

    Umesh B. Jagtap

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Aldeghi, M., Bluck, J.P., Biggin, P.C. (2018). Absolute Alchemical Free Energy Calculations for Ligand Binding: A Beginner’s Guide. In: Gore, M., Jagtap, U. (eds) Computational Drug Discovery and Design. Methods in Molecular Biology, vol 1762. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7756-7_11

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  • DOI: https://doi.org/10.1007/978-1-4939-7756-7_11

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