Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

Baz, Jörg; Gebhardt, Julia; Kraus, Hamzeh; Markthaler, Daniel; Hansen, Niels

doi:10.1002/cite.201800050

Cited by 13 publications

(29 citation statements)

References 150 publications

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“…9 (b). For simulations based on αCD, we conclude from the good agreement between the PMF-based estimates for ∆G • bind and the corresponding results from double decoupling [16,100] as well as direct counting [19] that simulation time was sufficient in order to remove any possible bias due to the initial host conformations. Moreover, the force field used in the present study does not show multiple conformations for αCD [103].…”

Section: Influence Of the Host's / Ligand's Flexibilitymentioning

confidence: 64%

“…The latter class of methods requires an integration of the PMF over a bound and unbound region, corresponding to the reversible work to transfer the ligand (or guest molecule) from the bulk to the binding pose inside the host. In principle, the PMF-derived estimate of the binding free enthalpy can be validated by results from double decoupling [16,17] or, when possible, by direct counting estimation, based on long unbiased simulations [18,19]. PMF calculations for a specific binding process, are based upon either equilibrium methods such as umbrella sampling [20,21], local elevation [22] or metadynamics [23], adaptive biasing force [24], forward flux sampling [25] or on non-equilibrium methods such as steered MD [26].…”

Section: Introductionmentioning

confidence: 99%

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Lessons Learned from the Calculation of One-Dimensional Potentials of Mean Force [Article v1.0]

2019

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The origins of different computational artifacts that may occur in the calculation of one-dimensional potentials of mean force (PMF) via umbrella sampling molecular dynamics simulations and manifest as free energy offset between bulk solvent regions are investigated. By systematic studies, three distinct causes are elucidated: (i) an unfortunate choice of reference points for the umbrella distance restraint; (ii) a misfit in probability distributions between bound and unbound umbrella windows in case of multiple binding modes; (iii) artifacts introduced by the free energy estimator. Starting with a fully symmetric model system consisting of methane binding to a cylindrical host, complexity is increased through the introduction of dipolar interactions between the host and the solvent, the host and the guest molecule or between all involved species, respectively. The manifestation of artifacts is illustrated and their origin and prevention is discussed. Finally, the consequences for the calculation of standard binding free enthalpies is illustrated using the complexation of primary alcohols with α-cyclodextrin as an example.

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Section: Influence Of the Host's / Ligand's Flexibilitymentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Lessons Learned from the Calculation of One-Dimensional Potentials of Mean Force [Article v1.0]

2019

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“…A simple free-energy calculation approach based on direct counting, [74][75][76][77] i. e., by monitoring equili-brium populations in an unbiased MD simulation, is inapplicable here. Reaching a sufficient number of interconversion transitions between VASE and KITE would require multi-millisecond simulations.…”

Section: Introductionmentioning

confidence: 99%

Vase‐Kite Equilibrium of Resorcin[4]arene Cavitands Investigated Using Molecular Dynamics Simulations with Ball‐and‐Stick Local Elevation Umbrella Sampling

Hahn

Milić

Hünenberger

2019

Helvetica Chimica Acta

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A key feature of resorcin[4]arene cavitands is their ability to switch between a closed/contracted (Vase) and an open/expanded (Kite) conformation. The mechanism and dynamics of this interconversion remains, however, elusive. In the present study, the Vase‐Kite transitions of a quinoxaline‐based and of a dinitrobenzene‐based resorcin[4]arene are investigated using molecular dynamics (MD) simulations in three environments (vacuum, chloroform, and toluene) and at three temperatures (198.15, 248.15, and 298.15 K). The challenge of sampling the Vase‐Kite transition, which occurs experimentally on the millisecond time scale, is overcome by calculating relative free energies using ball‐and stick local elevation umbrella sampling (B&S‐LEUS) to enhance the statistics on the relevant states and to promote interconversion transitions. Associated unbiased MD simulations also evidence for the first time a complete Vase‐to‐Kite transition, as well as transitions between degenerate Kite1 and Kite2 forms and solvent‐exchange events. The calculated Vase‐to‐Kite free‐energy changes ΔG are in qualitative agreement with the experimental magnitudes and trends. The level of quantitative agreement is, however, limited by the force‐field accuracy and, in particular, by the approximate treatment of intramolecular interactions at the classical level. The results are in line with a less stable Vase state for the dinitrobenzene compared to the quinoxaline compound, and a negative entropy change ΔS for the Vase‐to‐Kite transition of the latter compound. Relative free energies calculated for intermediates also suggest that the Vase‐Kite transition does not follow a concerted mechanism, but an asynchronous one with sequential opening of the flaps. In particular, the conformation involving two adjacent flaps open in a parallel direction (cis‐p) represents a likely intermediate, which has not been observed experimentally to date.

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“…In the unbiased approach, referred to as direct counting (DC), the occurrences of bound, N b , and unbound, N u , instances during long (t ≥ 10 µs) standard MD simulations of one host-guest pair solvated in a box of water are counted. The binding free enthalpy is then obtained from [32]…”

Section: Calculation Of Binding Free Enthalpies and Rate Constants In Bulk Solutionmentioning

confidence: 99%

“…with standard state volume V 0 = 1.661 nm 3 and average volume of the simulation box V box . In addition, average bound t b and unbound t u residence times can be calculated, yielding association k on and dissociation k off rates [32]…”

Section: Calculation Of Binding Free Enthalpies and Rate Constants In Bulk Solutionmentioning

confidence: 99%

An atomistic view on liquid phase adsorption

Kraus

Hansen

2021

Preprint

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The effect of immobilized β-cyclodextrin (bCD) molecules inside a mesoporous silica support on the uptake of benzene and p-nitrophenol from aqueous solution was investigated using all-atom molecular dynamics (MD) simulations. The calculated adsorption isotherms are discussed with respect to the free energies of binding for a 1:1 complex of bCD and the aromatic guest molecule. The adsorption capacity of the bCDcontaining material significantly exceeds the amount corresponding to a 1:1 binding scenario, in agreement with experimental observations for benzene adsorption. The demonstrated feasibility of classical all-atom MD simulations to calculate liquid phase adsorption isotherms paves the way to a molecular interpretation of experimental data that are too complex to be described by empirical models.

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Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

Cited by 13 publications

References 150 publications

Lessons Learned from the Calculation of One-Dimensional Potentials of Mean Force [Article v1.0]

Lessons Learned from the Calculation of One-Dimensional Potentials of Mean Force [Article v1.0]

Vase‐Kite Equilibrium of Resorcin[4]arene Cavitands Investigated Using Molecular Dynamics Simulations with Ball‐and‐Stick Local Elevation Umbrella Sampling

An atomistic view on liquid phase adsorption

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