Metadynamics supports molecular dynamics simulation-based binding affinities of eucalyptol and beta-cyclodextrin inclusion complexes

Nutho, Bodee; Nunthaboot, Nadtanet; Wolschann, Peter; Kungwan, Nawee; Rungrotmongkol, Thanyada

doi:10.1039/c7ra09387j

Cited by 27 publications

(15 citation statements)

References 79 publications

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“…The percentage of no flip angle correlates with M1, which is the most populated state during simulation, and the percentage of flip angle relates with M2 and M3, in which the glucopyranose subunits flip and the intramolecular hydrogen bonds of the wider CD rim disappear. Thus, glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have lower chance to flip (22-31% of flip angle) than in βCD (42% of flip angle), which is in agreement with their inclusion efficiency reported in our previous study [22]. Table 2.…”

Section: Structural Distortion Of Glucose Units In the Hpβcdssupporting

confidence: 89%

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Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Kerdpol

Kicuntod

Wolschann

et al. 2019

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2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. Understanding of the structural properties of HPβCD and its derivatives based on the number of 2-hydroxypropyl (HP) substituents at the a-D-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution called as 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have lower chance to flip than in βCD. Also, HP groups are occasionally blocking the hydrophobic cavity of HPβCDs, thus hindering the drug inclusion. We found that HPβCDs with high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitution are even more probable to be blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation based on our conformational analyses such as structural distortion, radius of gyration, circularity and cavity self-closure of the HPβCDs.

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Section: Structural Distortion Of Glucose Units In the Hpβcdssupporting

confidence: 89%

“…Normally, CD alkylations are observed at the O2 and O6 positions [13,17,18]. Therefore, HPCD with substitutions at O2 (the most acidic position) and O6 (the most accessible position) with different degrees of substitution have been intensively investigated [11,[13][14][15][16][19][20][21][22].…”

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confidence: 99%

Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Kerdpol

Kicuntod

Wolschann

et al. 2019

Preprint

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“…Normally, βCD alkylations are observed at the O2 and O6 positions [13,17,18]. Therefore, HPβCD with substitutions at O2 (the most acidic position) and O6 (the most accessible position) with different degrees of substitution have been intensively investigated [11,13,14,15,16,19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Cavity Closure of 2-Hydroxypropyl-β-Cyclodextrin: Replica Exchange Molecular Dynamics Simulations

et al. 2019

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2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. An understanding of the structural properties of HPβCD and its derivatives, based on the number of 2-hydroxypropyl (HP) substituents at the α-d-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution, called 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that the glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have a lower chance of flipping than in βCD. Also, HP groups occasionally block the hydrophobic cavity of HPβCDs, thus hindering drug inclusion. We found that HPβCDs with a high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitutions have an even higher probability of being blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation, based on our conformational analyses, such as structural distortion, the radius of gyration, circularity, and cavity self-closure of the HPβCDs.

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“…CDs are well suited for atomic resolution computational studies due to their small size and low number of degrees of freedom. A number of docking and computational studies involving CDs have been published [10][11][12]26] but the use of these tools is much less extended for these molecules than in protein, peptide, or lipid systems. Thus, the proposal and validation of reliable and efficient computational methods for CD systems is expected to contribute to acquire a better knowledge able to complement the interpretation of wet-lab measurements.…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, molecular dynamics (MD) simulations are increasingly popular because they can provide structural, energetic, dynamic, and even mechanistic information. Computational studies of CDs are not so common, although a significant number of works based on MD simulations and docking of these molecules have already been published [10][11][12]. The number of degrees of freedom of single (native or modified) CDs is much lower than that of typical macromolecules.…”

Section: Introductionmentioning

confidence: 99%

Rings, Hexagons, Petals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes

et al. 2020

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The basket-like geometry of cyclodextrins (CDs), with a cavity able to host hydrophobic groups, makes these molecules well suited for a large number of fundamental and industrial applications. Most of the established CD-based applications rely on trial and error studies, often ignoring key information at the atomic level that could be employed to design new products and to optimize their use. Computational simulations are well suited to fill this gap, especially in the case of CD systems due to their low number of degrees of freedom compared with typical macromolecular systems. Thus, the design and validation of solid and efficient methods to simulate and analyze CD-based systems is key to contribute to this field. The behavior of supramolecular complexes critically depends on the media where they are embedded, so the detailed characterization of the solvent is required to fully understand these systems. In the present work, we use the inclusion complex formed by two α-CDs and one sodium dodecyl sulfate molecule to test eight different parameterizations of the GROMOS and AMBER force fields, including several methods aimed to increase the conformational sampling in computational molecular dynamics simulation trajectories. The system proved to be extremely sensitive to the employed force field, as well as to the presence of a water/air interface. In agreement with previous experiments and in contrast to the results obtained with AMBER, the analysis of the simulations using GROMOS showed a quick adsorption of the complex to the interface as well as an extremely exotic behavior of the water molecules surrounding the structure both in the bulk aqueous solution and at the water surface. The chirality of the CD molecule seems to play an important role in this behavior. All together, these results are expected to be useful to better understand the behavior of CD-based supramolecular complexes such as adsorption or aggregation driving forces, as well as to introduce new methods able to speed up general MD simulations.

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Metadynamics supports molecular dynamics simulation-based binding affinities of eucalyptol and beta-cyclodextrin inclusion complexes

Abstract: The development of various molecular dynamics methods enables the detailed investigation of association processes, like host–guest complexes, including their dynamics and, additionally, the release of the guest compound.

Cited by 27 publications

References 79 publications

Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Cavity Closure of 2-Hydroxypropyl-β-Cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Rings, Hexagons, Petals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes

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Metadynamics supports molecular dynamics simulation-based binding affinities of eucalyptol and beta-cyclodextrin inclusion complexes

Abstract: The development of various molecular dynamics methods enables the detailed investigation of association processes, like host–guest complexes, including their dynamics and, additionally, the release of the guest compound.

Cited by 27 publications

References 79 publications

Cavity Closure of 2-Hydroxypropyl-&beta;-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Cavity Closure of 2-Hydroxypropyl-&beta;-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Cavity Closure of 2-Hydroxypropyl-β-Cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Rings, Hexagons, Petals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes

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Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations

Cavity Closure of 2-Hydroxypropyl-β-cyclodextrin: Replica Exchange Molecular Dynamics Simulations