Bennett acceptance ratio method to calculate the binding free energy of BACE1 inhibitors: Theoretical model and design of new ligands of the enzyme

Gutiérrez, Margarita; Vallejos, Gabriel; Cortés, Magdalena P.; Bustos, Carlos

doi:10.1111/cbdd.13456

Cited by 11 publications

(3 citation statements)

References 58 publications

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“…They are similar in that we are computing a free energy between two Hamiltonians, one in which an interaction is turned off. We could thus use similar techniques for computing these free energy differences, such as thermodynamic integration (Kirkwood, 1935;Bhati et al, 2019), BAR (Gutiérrez et al, 2019), MBAR (Shirts and Chodera, 2008;Bhati et al, 2019), or MM/PBSA (Rifai et al, 2019), although here we effectively use a simple free energy perturbation (FEP) expression (Zwanzig, 1954;Jorgensen and Thomas, 2008). The approaches are different in that we are only considering ensembles of structures where the interactions being turned off are relatively weak.…”

Section: Discussionmentioning

confidence: 99%

On Calculating Free Energy Differences Using Ensembles of Transition Paths

Hall

Dixon

Dickson

2020

Front. Mol. Biosci.

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Section: Discussionmentioning

confidence: 99%

On Calculating Free Energy Differences Using Ensembles of Transition Paths

Hall

Dixon

Dickson

2020

Front. Mol. Biosci.

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“…They are similar in that we are computing a free energy between two Hamiltonians, one in which an interaction is turned off. We could thus use similar techniques for computing these free energy differences, such as thermodynamic integration [54,55], BAR [56], MBAR [36,55], or MM/PBSA [57], although here we effectively use a simple free energy perturbation (FEP) expression [58,59]. The approaches are different in that we are only considering ensembles of structures where the interactions being turned off are relatively weak.…”

Section: Discussionmentioning

confidence: 99%

Correction Terms for Calculating Binding Free Energy Using Rates from Nonequilibrium Simulations

Hall¹,

Dixon²,

Dickson³

2020

Preprint

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<div>The free energy of a process is the fundamental quantity that determines its spontaneity or propensity at a given temperature. Binding free energy of a drug candidate to its biomolecular target is used as an objective quantity in drug design. Binding kinetics -- rates of association (k<sub>on</sub>) and dissociation (k<sub>off</sub>) -- have also demonstrated utility for their ability to predict efficacy and in some cases have been shown to be more predictive than the binding free energy alone. Although challenging, some methods exist to calculate binding kinetics from molecular simulations. While the kinetics of the binding process are related to the free energy by the log of their ratio, it is not straightforward to account for common, practical details pertaining to the calculation of rates in molecular simulations, such as the finite simulation volume or the particular definition of the ``bound" and ``unbound" states. Here we derive a set of correction terms that can be applied to calculations of binding free energies using rates observed in simulations. One term accounts for the particular definitions of the bound and unbound states. The second term accounts for residual electrostatic interactions that might still be present between the molecules, which is especially useful if one or both of the molecules carry an explicit charge. The third term accounts for the volume of the unbound state in the simulation box, which is useful to keep the simulated volume as small as possible during rate calculations. We apply these correction terms to revisit the calculation of binding free energies from rate constants for a host-guest system that was part of a blind prediction challenge, where significant deviations were observed between free energies calculated with rate ratios and those calculated from alchemical perturbation. The correction terms combine to significantly decrease the error with respect to computational benchmarks, from 3.4 to 0.76 kcal/mol.</div>

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“…These lambda points serve as critical milestones in the exploration of ligand-protein interactions and contribute to the overall robustness of our free energy perturbation simulations. The Bennett Acceptance Ratio (BAR) method with the appropriate flags was employed to analyze the results of FEP [58].…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Human Plasma Butyrylcholinesterase Hydrolyzes Atropine: Kinetic and Molecular Modeling Studies

Mukhametgalieva,

Mir,

Shaihutdinova

et al. 2024

Molecules

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The participation of butyrylcholinesterase (BChE) in the degradation of atropine has been recurrently addressed for more than 70 years. However, no conclusive answer has been provided for the human enzyme so far. In the present work, a steady-state kinetic analysis performed by spectrophotometry showed that highly purified human plasma BChE tetramer slowly hydrolyzes atropine at pH 7.0 and 25 °C. The affinity of atropine for the enzyme is weak, and the observed kinetic rates versus the atropine concentration was of the first order: the maximum atropine concentration in essays was much less than Km. Thus, the bimolecular rate constant was found to be kcat/Km = 7.7 × 104 M−1 min−1. Rough estimates of catalytic parameters provided slow kcat < 40 min−1 and high Km = 0.3–3.3 mM. Then, using a specific organophosphoryl agent, echothiophate, the time-dependent irreversible inhibition profiles of BChE for hydrolysis of atropine and the standard substrate butyrylthiocholine (BTC) were investigated. This established that both substrates are hydrolyzed at the same site, i.e., S198, as for all substrates of this enzyme. Lastly, molecular docking provided evidence that both atropine isomers bind to the active center of BChE. However, free energy perturbations yielded by the Bennett Acceptance Ratio method suggest that the L-atropine isomer is the most reactive enantiomer. In conclusion, the results provided evidence that plasma BChE slowly hydrolyzes atropine but should have no significant role in its metabolism under current conditions of medical use and even under administration of the highest possible doses of this antimuscarinic drug.

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Bennett acceptance ratio method to calculate the binding free energy of BACE1 inhibitors: Theoretical model and design of new ligands of the enzyme

Cited by 11 publications

References 58 publications

On Calculating Free Energy Differences Using Ensembles of Transition Paths

On Calculating Free Energy Differences Using Ensembles of Transition Paths

Correction Terms for Calculating Binding Free Energy Using Rates from Nonequilibrium Simulations

Human Plasma Butyrylcholinesterase Hydrolyzes Atropine: Kinetic and Molecular Modeling Studies

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