Calculation of the relative binding free energy of 2′GMP and 2′AMP to ribonuclease T1 using molecular dynamics/free energy perturbation approaches

1990 ◽  
Vol 212 (1) ◽  
pp. 197-209 ◽  
Author(s):  
Shuichi Hirono ◽  
Peter A. Kollman
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Perturbation ◽  
Ribonuclease T1 ◽  
Relative Binding ◽  
Energy Perturbation

scholarly journals Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision and Reproducibility

2021 ◽  
Author(s):  
Alexander Wade ◽  
Agastya Bhati ◽  
Shunzhou Wan ◽  
Peter Coveney
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Thermodynamic Integration ◽  
Free Energy Perturbation ◽  
Free Energies ◽  
Ensemble Averaging ◽  
Relative Binding ◽  
Energy Perturbation ◽  
Binding Free Energies

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat myriad diseases. In this work we examine the computation of alchemical relative binding free energies with an eye to assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2 and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2 and NAMD3. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between packages of 0.5 $kcal/mol$ The correlation between packages is very good with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficient between two packages being 0.91, 0.89 and 0.74 respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.

Predicting the affinity of halogenated reversible covalent inhibitors through relative binding free energy

2019 ◽  
Vol 21 (44) ◽  
pp. 24723-24730 ◽  
Author(s):  
Jerônimo Lameira ◽  
Vinícius Bonatto ◽  
Lorenzo Cianni ◽  
Fernanda dos Reis Rocho ◽  
Andrei Leitão ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Cathepsin L ◽  
Free Energy Perturbation ◽  
Relative Binding ◽  
Covalent Inhibitors ◽  
Human Cathepsin ◽  
Energy Perturbation ◽  
Reversible Covalent

The free energy perturbation using the covalent and noncovalent states can predict the binding affinity of covalent halogenated dipeptidyl nitrile inhibitors of the human Cathepsin L (hCatL).

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