Direct Comparison of Experimental and Calculated Folding Free Energies for Hydrophobic Deletion Mutants of Chymotrypsin Inhibitor 2:  Free Energy Perturbation Calculations Using Transition and Denatured States from Molecular Dynamics Simulations of Unfolding†

Biochemistry ◽  
2001 ◽  
Vol 40 (9) ◽  
pp. 2723-2731 ◽  
Author(s):  
YongPing Pan ◽  
Valerie Daggett
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Free Energy Perturbation ◽  
Deletion Mutants ◽  
Free Energies ◽  
Chymotrypsin Inhibitor ◽  
Chymotrypsin Inhibitor 2 ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Denatured States

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.

scholarly journals Effect of mutations on binding of ligands to guanine riboswitch probed by free energy perturbation and molecular dynamics simulations

2019 ◽  
Vol 47 (13) ◽  
pp. 6618-6631 ◽  
Author(s):  
Jianzhong Chen ◽  
Xingyu Wang ◽  
Laixue Pang ◽  
John Z H Zhang ◽  
Tong Zhu
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Drug Targets ◽  
Md Simulations ◽  
Free Energy Perturbation ◽  
Potential Drug ◽  
Free Energy Decomposition ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Potential Drug Targets

Abstract Riboswitches can regulate gene expression by direct and specific interactions with ligands and have recently attracted interest as potential drug targets for antibacterial. In this work, molecular dynamics (MD) simulations, free energy perturbation (FEP) and molecular mechanics generalized Born surface area (MM-GBSA) methods were integrated to probe the effect of mutations on the binding of ligands to guanine riboswitch (GR). The results not only show that binding free energies predicted by FEP and MM-GBSA obtain an excellent correlation, but also indicate that mutations involved in the current study can strengthen the binding affinity of ligands GR. Residue-based free energy decomposition was applied to compute ligand-nucleotide interactions and the results suggest that mutations highly affect interactions of ligands with key nucleotides U22, U51 and C74. Dynamics analyses based on MD trajectories indicate that mutations not only regulate the structural flexibility but also change the internal motion modes of GR, especially for the structures J12, J23 and J31, which implies that the aptamer domain activity of GR is extremely plastic and thus readily tunable by nucleotide mutations. This study is expected to provide useful molecular basis and dynamics information for the understanding of the function of GR and possibility as potential drug targets for antibacterial.

Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field

2010 ◽  
Vol 6 (5) ◽  
pp. 1509-1519 ◽  
Author(s):  
Devleena Shivakumar ◽  
Joshua Williams ◽  
Yujie Wu ◽  
Wolfgang Damm ◽  
John Shelley ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Force Field ◽  
Free Energy Perturbation ◽  
Free Energies ◽  
Energy Perturbation ◽  
Solvation Free Energies

scholarly journals Prediction of Accurate Binding Modes using Combination of classical and accelerated Molecular dynamics and Free Energy Perturbation Calculations: An Application to Toxicity Studies

2018 ◽  
Author(s):  
Filip Fratev ◽  
Thomas Steinbrecher ◽  
Svava Ósk Jónsdóttir
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ligand Binding ◽  
Protein Dynamics ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Free Energy Perturbation ◽  
Binding Modes ◽  
Free Energies ◽  
Energy Perturbation

AbstractEstimating the correct binding modes of ligands in protein-ligand complexes is not only crucial in the drug discovery process, but also for elucidating potential toxicity mechanisms. In the current paper, we discuss and demonstrate a computational modelling protocol using the combination of docking, classical (cMD) and accelerated (aMD) molecular dynamics and free energy perturbation (FEP+ protocol) for identification of the binding modes of selected perfluorocarboxyl acids (PFCAs) in the PPARγ nuclear receptor.Initially, we employed both the regular and induced fit docking which failed to correctly predict the ligand binding modes and rank the compounds with respect to experimental free energies of binding, when they were docked into non-native X-ray structure. The cMD and aMD simulations identified the presence of multiple binding modes for these compounds, and the shorter chain PFCAs (C6-C8) continuously moved between a few energetically favourable binding conformations. These results demonstrate that the docking scoring function cannot rank compounds precisely in such cases, not due to its insufficiency, but because of the use of incorrect or only one unique bindings pose, neglecting the protein dynamics. Finally, based on MD predictions of binding conformations, the FEP+ sampling protocol was extended and then accurately reproduced experimental differences in the free energies. Thus, the preliminary MD simulations can also provide helpful information about correct set-up of the FEP+ calculations. These results show that the PFCAs binding modes were accurately predicted and the FEP+ protocol can be used to estimate free energies of binding of flexible molecules outside of typical drug-like compounds.Our in silico workflow revealed the main characteristics of the PFCAs, which are week PPARγ partial agonists and illustrated the importance of specific ligand-residue interactions within the LBD. This work also suggests a common workflow for identification of ligand binding modes, ligand-protein dynamics description and relative free energy calculations.

scholarly journals Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility

2020 ◽  
Vol 11 (8) ◽  
pp. 2269-2276 ◽  
Author(s):  
Kerstin Wallraven ◽  
Fredrik L. Holmelin ◽  
Adrian Glas ◽  
Sven Hennig ◽  
Andrey I. Frolov ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Receptor Binding ◽  
Free Ligand ◽  
Macrocyclic Ligands ◽  
Free Energy Perturbation ◽  
Direct Binding ◽  
Energy Perturbation ◽  
Dynamics Simulations

A combination of free energy perturbations and molecular dynamics simulations were applied to investigate large macrocyclic ligands and their receptor binding.

scholarly journals Solvation Free Energy of Protonated Lysine: Molecular Dynamics Study

2021 ◽  
Vol 7 (2) ◽  
pp. 69-75
Author(s):  
S. P. Khanal ◽  
B. Poudel ◽  
R. P. Koirala ◽  
N. P. Adhikari
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Energy Difference ◽  
Solvation Free Energy ◽  
Free Energy Perturbation ◽  
Free Energy Difference ◽  
Free Energy Of Solvation ◽  
Acceptance Ratio ◽  
Energy Perturbation ◽  
Dynamics Simulations

In the present work, we have used an alchemical approach for calculating solvation free energy of protonated lysine in water from molecular dynamics simulations. These approaches use a non-physical pathway between two end states in order to compute free energy difference from the set of simulations. The solute is modeled using bonded and non-bonded interactions described by OPLS-AA potential, while four different water models: TIP3P, SPC, SPC/E and TIP4P are used. The free energy of solvation of protonated lysine in water has been estimated using thermodynamic integration, free energy perturbation, and Bennett acceptance ratio methods at 310 K temperature. The contributions to the free energy due to van der Waals and electrostatics parameters are also separately computed. The estimated values of free energy of solvation using different methods are in well agreement with previously reported experimental value within 14 %.

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