Prediction of Ligand Transport along Hydrophobic Enzyme Nanochannels

Escalante, Diego E.; Aksan, Alptekin

doi:10.1016/j.csbj.2019.06.001

Cited by 2 publications

(10 citation statements)

References 18 publications

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“…The accuracy of the model, published elsewhere, is 90%, and it is up to 6 orders of magnitude faster than all-atom methods. 1…”

Section: ■ Discussionmentioning

confidence: 99%

“…The BB geometries and the thermodynamic results presented have successfully been used elsewhere to develop a model that can predict the transport of ligands through nanochannels found in broad-substrate specificity enzymes. 1 ■ ASSOCIATED CONTENT * S Supporting Information…”

Section: ■ Conclusionmentioning

confidence: 99%

“…This increases the computational cost substantially to 10 3 −10 5 s per ligand per enzyme. 1 In an attempt to reduce the computational time, some simulations have used implicit solvent models, 33 while others have ignored the presence of water molecules inside channels. 18 These approaches therefore do not account for the effect of water−water hydrogen bonding on ligand transport, which we show here to be a very important factor.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The digitization technique we developed here has been successfully applied to the channel of naphthalene 1,2dioxygenase, a BSS enzyme in a very recent sister publication. 1 The nonbonded interaction strength of the BB walls, characterized by the Lennard-Jones potential well depth, ε C , was tuned to adjust hydrophobicity. Six different ε C levels were chosen to cover the full range of hydrophobicity exhibited in BSS enzymes.…”

Section: ■ Introductionmentioning

confidence: 99%

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Role of Water Hydrogen Bonding on Transport of Small Molecules inside Hydrophobic Channels

Escalante

Aksan

2019

J. Phys. Chem. B

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We conducted a systematic analysis of water networking inside smooth hyperboloid hydrophobic structures (cylindrical, barrel, and hourglass shapes) to elucidate the role of water hydrogen bonding on the transport of small hydrophobic molecules (ligands). Through a series of molecular dynamics simulations, we established that a hydrogen-bonded network forming along the centerline resulted in a water exclusion zone adjacent to the walls. The size of the exclusion zone is a function of the geometry and the nonbonded interaction strength, defining the effective hydrophobicity of the structure. Exclusion of water molecules from this zone results in lower apparent viscosity, leading to acceleration of ligand transport up to 7 times faster than that measured in the bulk. Transport of ligands into and out of the hydrophobic structures was shown to be controlled by a single water molecule that capped the narrow regions in the structure. This mechanism provides physical insights into the behavior and role of water in the bottleneck regions of hydrophobic enzyme channels. These findings were then used in a sister publication [Escalante, D. E., et al.Comput. Struct. Biotechnol. J.201917757760] to develop a model that can accurately predict the transport of ligands along nanochannels of broad-substrate specificity enzymes.

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“…The accuracy of the model, published elsewhere, is 90%, and it is up to 6 orders of magnitude faster than all-atom methods. 1…”

Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Water Hydrogen Bonding on Transport of Small Molecules inside Hydrophobic Channels

Escalante

Aksan

2019

J. Phys. Chem. B

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“…To further explore this idea, we took advantage of the available structures of colchicine-bound tubulin (TC), unliganded soluble tubulin (Tub), and polymerized tubulin (Tubs) to quantify the accessibility of the binding channel of colchicine, as previously described (66). We used drug transport modeling method for colchicine transport because it has successfully predicted the transport of contaminants through several degradation enzymes (101), and ligand transport along hydrophobic enzymes (102), with binding channels similar to the hydrophobic binding pocket buried inside tubulin. Table 1 for the GTP-state tubulin, the average channel length varies significantly depending on the conformation of tubulin.…”

Section: Colchicine Can Mainly Bind To Free Tubulin In a Curved Confomentioning

confidence: 99%

Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine

Hemmat

Braman

Escalante

et al. 2020

Preprint

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Microtubule-directed anti-cancer drugs, such as paclitaxel, vinblastine, and colchicine, disrupt cell mitosis through suppression of microtubule dynamics ("kinetic stabilization"). However, while the molecular mechanisms of paclitaxel and vinblastine act as pseudoand true-kinetic stabilizers, respectively, the molecular mechanism of colchicine has remained enigmatic since it requires explanation of both the slow kinetics of the drug and suppression of microtubule dynamics. In this work, we applied an integrated multi-scale modeling-experimental approach to systematically characterize the microtubule targeting agent (MTA) colchicine. We found that colchicine stabilizes microtubule dynamics significantly both in vivo and in vitro in a time and concentration-dependent manner. Molecular modeling results suggest that tubulin's binding pocket is accessible to the drug for only 15% of the simulation trajectory time in straight and 82% in curved conformation on average, confirming that colchicine mainly binds to free tubulin. Molecular dynamics simulations show that there are conformational changes at longitudinal and lateral residues of GTP-tubulin-colchicine compared to a lattice tubulin structure, explaining why further incorporation of tubulin dimers to a tubulin-colchicine complex at a protofilament tip is unfavorable. Thermokinetic modeling of microtubule assembly shows that colchicine bound at fractions as low as ~0.008 to free tubulin can poison the ends of protofilaments with a Poisson distribution and thus, reduce the microtubule growth rate, while stabilizing the tubulin lateral bond and reducing the microtubule shortening rate, i.e. true kinetic stabilization. This study suggests new strategies for colchicine administration to improve the therapeutic window in the treatment of cancer and inflammatory diseases. Significance StatementColchicine is an ancient microtubule targeting agent (MTA) known to attenuate microtubule (MT) dynamics but its cancer treatment efficacy is often limited by lack of a detailed understanding of the drug's mechanism of action. The primary goal of this study was to perform a multi-scale systematic analysis of molecular mechanism of action of colchicine. The analysis indicates that unlike paclitaxel and vinblastine, colchicine poisons the ends of protofilaments of MTs at low fractions bound to tubulin, in a time-dependent manner. Our results suggest new insights into improvement of the clinical administration of colchicine and new colchicine-site inhibitors.

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Prediction of Ligand Transport along Hydrophobic Enzyme Nanochannels

Cited by 2 publications

References 18 publications

Role of Water Hydrogen Bonding on Transport of Small Molecules inside Hydrophobic Channels

Role of Water Hydrogen Bonding on Transport of Small Molecules inside Hydrophobic Channels

Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine

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