QM/MM Free-Energy Perturbation Compared to Thermodynamic Integration and Umbrella Sampling:  Application to an Enzymatic Reaction

2006 ◽  
Vol 2 (2) ◽  
pp. 452-461 ◽  
Author(s):  
Johannes Kästner ◽  
Hans Martin Senn ◽  
Stephan Thiel ◽  
Nikolaj Otte ◽  
Walter Thiel
Keyword(s):  
Free Energy ◽  
Enzymatic Reaction ◽  
Umbrella Sampling ◽  
Thermodynamic Integration ◽  
Free Energy Perturbation ◽  
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.

Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling

2017 ◽  
Vol 19 (44) ◽  
pp. 30239-30248 ◽  
Author(s):  
Jianzhong Chen ◽  
Jinan Wang ◽  
Weiliang Zhu
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Anaplastic Lymphoma Kinase ◽  
Drug Target ◽  
Umbrella Sampling ◽  
Free Energy Perturbation ◽  
Drug Resistant ◽  
Anaplastic Lymphoma ◽  
Energy Perturbation ◽  
Different Levels

Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors.

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