scholarly journals Estimating thermodynamic expectations and free energies in expanded ensemble simulations: Systematic variance reduction through conditioning

2017 ◽  
Vol 146 (19) ◽  
pp. 194101 ◽  
Author(s):  
Manuel Athènes ◽  
Pierre Terrier
Keyword(s):  
Variance Reduction ◽  
Free Energies ◽  
Ensemble Simulations ◽  
Expanded Ensemble

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

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