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Free Energy Calculations in Biological Systems. How Useful Are They in Practice?

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New Algorithms for Macromolecular Simulation

Part of the book series: Lecture Notes in Computational Science and Engineering ((LNCSE,volume 49))

Abstract

Applications of molecular simulations targeted at the estimation of free energies are reviewed, with a glimpse into their promising future. The methodological milestones paving the road of free energy calculations are summarized, in particular free energy perturbation and thermodynamic integration, in the framework of constrained or unconstrained molecular dynamics. The continuing difficulties encountered when attempting to obtain accurate estimates are discussed with an emphasis on the usefulness of large-scale numerical simulations in non-academic environments, like the world of the pharmaceutical industry. Applications of the free energy arsenal of methods is illustrated through a variety of biologically relevant problems, among which the prediction of protein-ligand binding constants, the determination of membrane-water partition coefficients of small, pharmacologically active compounds — in connection with the blood-brain barrier, the folding of a short hydrophobic peptide, and the association of transmembrane α-helical domains, in line with the “two-stage” model of membrane protein folding. Current strategies for improving the reliability of free energy calculations, while making them somewhat more affordable, and, therefore, more compatible with the constraints of an industrial environment, are outlined.

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Authors and Affiliations

  1. Equipe de dynamique des assemblages membranaires, UMR CNRS/UHP 7565, Institut nancéien de chimie moléculaire, Université Henri Poincaré, BP 239, 54506, Vandoeuvre-lès-Nancy cedex, France

    Christophe Chipot

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  1. Christophe Chipot
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Editors and Affiliations

  1. Department of Mathematics, University of Leicester, University Road, Leicester, LE1 7RH, UK

    Benedict Leimkuhler

  2. Institut nancéien de chimie moléculaire, Université Henri Poincaré - Nancy I, B.P. 239, 54506, Vandoeuvre-lès-Nancy, France

    Christophe Chipot

  3. Department of Computer Science, Cornell University, 4130 Upson Hall, Ithaca, NY, 14853-7501, USA

    Ron Elber

  4. Arrhenius Laboratory Division of Physical Chemistry, Stockholm University, 106 91, Stockholm, Sweden

    Aatto Laaksonen

  5. Laboratory of Biophysical Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands

    Alan Mark

  6. Department of Chemistry, Courant Institute of Mathematical Sciences, New York University, Mercer Street 251, New York, NY, 10012, USA

    Tamar Schlick

  7. FB Mathematik und Informatik, Freie Universität Berlin, Arnimallee 2-6, 14195, Berlin, Germany

    Christoph Schütte

  8. Department of Computer Science, Purdue University, N. University Street 250, West Lafayette, IN, 47907-2066, USA

    Robert Skeel

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Chipot, C. (2006). Free Energy Calculations in Biological Systems. How Useful Are They in Practice?. In: Leimkuhler, B., et al. New Algorithms for Macromolecular Simulation. Lecture Notes in Computational Science and Engineering, vol 49. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-31618-3_12

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  • DOI: https://doi.org/10.1007/3-540-31618-3_12

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