
Contents
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3.1 Introduction 3.1 Introduction
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3.2 Performing probabilistic molecular dynamics simulations 3.2 Performing probabilistic molecular dynamics simulations
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3.3 Free energy calculations in biology and medicine: endpoint methods and alchemical methods 3.3 Free energy calculations in biology and medicine: endpoint methods and alchemical methods
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3.3.1 End state methods 3.3.1 End state methods
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3.3.2 Ensemble-based alchemical methods 3.3.2 Ensemble-based alchemical methods
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3.3.2.1 Equilibrium relative binding free energies 3.3.2.1 Equilibrium relative binding free energies
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3.3.2.2 Equilibrium absolute binding free energies 3.3.2.2 Equilibrium absolute binding free energies
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3.3.2.3 Non-equilibrium relative binding free energies 3.3.2.3 Non-equilibrium relative binding free energies
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3.3.2.4 Non-equilibrium absolute binding free energies 3.3.2.4 Non-equilibrium absolute binding free energies
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3.4 Ensemble size: reliability and reproducibility 3.4 Ensemble size: reliability and reproducibility
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3.4.1 Non-Gaussian distributions 3.4.1 Non-Gaussian distributions
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3.4.2 Size of ensembles and duration of simulations 3.4.2 Size of ensembles and duration of simulations
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3.5 ‘Enhanced sampling methods’ based on replica exchange 3.5 ‘Enhanced sampling methods’ based on replica exchange
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3.6 Summary 3.6 Summary
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3 Ensemble-based Molecular Dynamics Simulations and Free Energies
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Published:April 2025
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Abstract
This chapter focuses on ensemble-based molecular dynamics simulations and their crucial role in calculating free energies in biological and medical contexts. The chapter begins with an introduction to the principles of probabilistic molecular dynamics simulations, followed by an in-depth discussion on various methods for free energy calculations, including endpoint and alchemical methods. A detailed evaluation of equilibrium and non-equilibrium relative and absolute binding free energies is provided, along with recommendations for optimizing the performance of these methods. The importance of ensemble size for the reliability and reproducibility of simulations is examined, with special attention to non-Gaussian distributions and the impact of ensemble size and simulation duration. The chapter also covers enhanced sampling methods based on replica-exchange techniques. The conclusions summarize the key insights and their implications for the field of molecular dynamics.
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