Force Field Parameterization for the Description of the Interactions between Hydroxypropyl-β-Cyclodextrin and Proteins

Arsiccio, Andrea; Rospiccio, Marcello; Shea, Joan–Emma; Pisano, Roberto

doi:10.1021/acs.jpcb.1c04033

Cited by 12 publications

(13 citation statements)

References 53 publications

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“…Cyclodextrins are characterized by the presence of a lipophilic cavity and a hydrophilic outer surface, and it is well known in the literature that cyclodextrins can include apolar and aromatic groups within their cavity. − If it were true that cyclodextrins could at least partly embed lipophilic amino acid side chains from the protein into their ring cavity, the unfolded state could be stabilized by these complex formations because it exposes more apolar/aromatic residues. The shift of the equilibrium toward the unfolded state could therefore be explained by specific, direct interactions between the protein lipophilic residues and the cyclodextrin …”

Section: Resultsmentioning

confidence: 99%

Thermodynamic Modeling and Experimental Data Reveal That Sugars Stabilize Proteins According to an Excluded Volume Mechanism

Arsiccio,

Sarter,

Polidori

et al. 2023

J. Am. Chem. Soc.

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We present a new thermodynamic model to investigate the relative effects of excluded volume and soft interaction contributions in determining whether a cosolute will either destabilize or stabilize a protein in solution. This model is unique in considering an atomistically detailed model of the protein and accounting for the preferential accumulation/exclusion of the osmolyte molecules from the protein surface. Importantly, we use molecular dynamics simulations and experiments to validate the model. The experimental approach presents a unique means of decoupling excluded volume and soft interaction contributions using a linear polymeric series of cosolutes with different numbers of glucose subunits, from 1 (glucose) to 8 (maltooctaose), as well as an 8-mer of glucose units in the closed form (γ-CD). By studying the stabilizing effect of cosolutes along this polymeric series using lysozyme as a model protein, we validate the thermodynamic model and show that sugars stabilize proteins according to an excluded volume mechanism.

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Section: Resultsmentioning

confidence: 99%

Thermodynamic Modeling and Experimental Data Reveal That Sugars Stabilize Proteins According to an Excluded Volume Mechanism

Arsiccio,

Sarter,

Polidori

et al. 2023

J. Am. Chem. Soc.

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“…The g k , sc tr ( T ) and g bb tr ( T ) values (to be inserted into eq ) for a temperature of 310 K were obtained from our previous work of temperature-induced conformational transitions in implicit solvent and are listed in Table S1. The g k , sc tr ( c ) and g bb tr ( c ) values (to be inserted into eq ) for the different cosolutes considered in this work (urea, TMAO, sucrose and HPβCD) were taken either from the work by Bolen and co-workers ,− and Moeser and Horinek or from our computational investigation of HPβCD and are listed in Table S2.…”

Section: Methodsmentioning

confidence: 99%

“…For HPβCD, we obtained the transfer free energy values from our prior computational work, 69 as detailed in the Supporting Information. The force field employed for HBβCD in our previous work was based on the ADD description for sugars 71 that was developed with the specific aim to guarantee a reliable prediction of transfer free energies in ternary protein−water−cosolute mixtures.…”

Section: The Transfer Free Energy-based Simulations Predict the Aggre...mentioning

confidence: 99%

Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach

et al. 2023

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The intrinsically disordered protein Tau represents the main component of neurofibrillary tangles that are a hallmark of Alzheimer's disease. A small fragment of Tau, known as paired helical filament 6 (PHF6), is considered to be important for the formation of the β-structure core of the fibrils. Here we study the aggregation of this fragment in the presence of different cosolutes, including urea, TMAO, sucrose and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD), using both experiments and molecular dynamics simulations. A novel implicit solvation approach (MIST -Model with Implicit Solvation Thermodynamics) is used, where an energetic contribution based on the concept of transfer free energies describes the effect of the cosolutes. The simulation predictions are compared to thioflavin-T and atomic force microscopy results, and the good agreement observed confirms the predictive ability of the computational approach herein proposed. Both simulations and experiments indicate that PHF6 aggregation is inhibited in the presence of urea and 2-HPβCD, while TMAO and sucrose stabilize associated conformations. The remarkable ability of HPβCD to inhibit aggregation represents an extremely promising result for future applications, especially considering the widespread use of this molecule as a drug carrier to the brain and as a solubilizer/excipient in pharmaceutical formulations.

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“…To model the systems the CHARMM General Force Field (CGenFF) was used to model QUE [ 69 ], and 2HP-β-CD and 2,6Me-β-CD were parameterized using the ADD force-field [ 70 ]. Each QUE/CD complex was solvated using the TIP3P water model [ 71 ] in a cubic box ensuring a minimum distance of 15 Å between each complex atom and the edge of the periodic box.…”

Section: Methodsmentioning

confidence: 99%

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-β-cyclodextrin and 2,6-Methylated-β-cyclodextrin

et al. 2022

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Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-β-cyclodextrin (2HP-β-CD) and 2,6-methylated cyclodextrin (2,6Me-β-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-β-CD and 2,6Μe-β-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-β-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-β-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-β-CD and 2HP-β-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-β-CD (520 M−1) and 2,6Me-β-CD (770 M−1). Thus, we propose that both formulations (2HP-β-CD:quercetin, 2,6Me-β-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies.

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Force Field Parameterization for the Description of the Interactions between Hydroxypropyl-β-Cyclodextrin and Proteins

Cited by 12 publications

References 53 publications

Thermodynamic Modeling and Experimental Data Reveal That Sugars Stabilize Proteins According to an Excluded Volume Mechanism

Thermodynamic Modeling and Experimental Data Reveal That Sugars Stabilize Proteins According to an Excluded Volume Mechanism

Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-β-cyclodextrin and 2,6-Methylated-β-cyclodextrin

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