Calculation of Relative Binding Free Energy Difference of DHFR Inhibitors by a Finite Difference Thermodynamic Integration (FDTI) Approach

1999 ◽  
Vol 16 (6) ◽  
pp. 1239-1244 ◽  
Author(s):  
Shantaram Kamath ◽  
Evans Coutinho ◽  
Prashant Desai
Keyword(s):  
Free Energy ◽  
Finite Difference ◽  
Binding Free Energy ◽  
Energy Difference ◽  
Thermodynamic Integration ◽  
Free Energy Difference ◽  
Relative Binding ◽  
Dhfr Inhibitors

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.

On the relationship between free energy difference calculations by thermodynamic integration and harmonic frequency analysis

2009 ◽  
Vol 87 (3) ◽  
pp. 496-501
Author(s):  
Jason Jechow ◽  
Tom Ziegler
Keyword(s):  
Free Energy ◽  
Statistical Mechanics ◽  
Frequency Analysis ◽  
Helmholtz Free Energy ◽  
Energy Difference ◽  
Thermodynamic Integration ◽  
Point Of View ◽  
Harmonic Frequency ◽  
Free Energy Difference ◽  
The Relationship

Harmonic frequency analysis (HFA), based on statistical mechanics, is a widely used and powerful tool for evaluating free energy changes between molecular states. It has, as such, been employed extensively to evaluate the free energy of reaction and activation for chemical processes. Alternatively, free energy differences can be calculated using thermodynamic integration (TI). In TI, the force on a constrained reaction coordinate is calculated, and this force from a to b is integrated to obtain the Helmholtz free energy change ΔAab. Although HFA and TI clearly are related from a fundamental statistical mechanics point-of-view, the relationship is not immediately obvious when one considers the quite different procedures applied in the two methods. This article provides a detailed analysis and proof of the relation between HFA and TI.

scholarly journals TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing

2021 ◽  
Vol 17 (2) ◽  
pp. 1250-1265
Author(s):  
Mateusz K. Bieniek ◽  
Agastya P. Bhati ◽  
Shunzhou Wan ◽  
Peter V. Coveney
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Relative Binding
Sign in / Sign up

Export Citation Format

Share Document