Unravelling the mechanism of glucose binding in a protein-based fluorescence probe: molecular dynamics simulation with a tailor-made charge model

Pang, Ziwei; Sokolov, M.V.; Kubař, Tomáš; Elstner, Marcus

doi:10.1039/d1cp03733a

Cited by 2 publications

(2 citation statements)

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“…Well-tempered metadynamics has been widely used to explore the pathways for the binding or unbinding of ligands to receptors ( Dodda et al, 2019 ; Ghosh et al, 2019 ; Brandt et al, 2021 ; Pang et al, 2022 ). Well-tempered metadynamics was used to calculate the two-dimensional free energy landscapes for the binding of the tweezer to all surface lysine residues ( Supplementary Figure S6 ).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

et al. 2022

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Using supramolecules for protein function regulation is an effective strategy in chemical biology and drug discovery. However, due to the presence of multiple binding sites on protein surfaces, protein function regulation via selective binding of supramolecules is challenging. Recently, the functions of 14-3-3 proteins, which play an important role in regulating intracellular signaling pathways via protein–protein interactions, have been modulated using a supramolecular tweezer, CLR01. However, the binding mechanisms of the tweezer molecule to 14-3-3 proteins are still unclear, which has hindered the development of novel supramolecules targeting the 14-3-3 proteins. Herein, the binding mechanisms of the tweezer to the lysine residues on 14-3-3σ (an isoform in 14-3-3 protein family) were explored by well-tempered metadynamics. The results indicated that the inclusion complex formed between the protein and supramolecule is affected by both kinetic and thermodynamic factors. In particular, simulations confirmed that K214 could form a strong binding complex with the tweezer; the binding free energy was calculated to be −10.5 kcal·mol−1 with an association barrier height of 3.7 kcal·mol−1. In addition, several other lysine residues on 14-3-3σ were identified as being well-recognized by the tweezer, which agrees with experimental results, although only K214/tweezer was co-crystallized. Additionally, the binding mechanisms of the tweezer to all lysine residues were analyzed by exploring the representative conformations during the formation of the inclusion complex. This could be helpful for the development of new inhibitors based on tweezers with more functions against 14-3-3 proteins via modifications of CLR01. We also believe that the proposed computational strategies can be extended to understand the binding mechanism of multi-binding sites proteins with supramolecules and will, thus, be useful toward drug design.

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Section: Resultsmentioning

confidence: 99%

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

et al. 2022

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“…We note that force fields using fixed point charges, however, may have difficulties in describing strongly hydrogen-bonded complexes and therefore that equilibrating the protein structure using such force fields may lead to conformations that are not suitable for further QM/MM investigations; this problem was described recently for the ChR2 protein (50), as well as for a glucose binding protein (104). Due to the long sampling times that are necessary, the system then requires using either a polarizable force field (104) or a semiempirical QM/MM approach, which has been shown to retain the active site structure well (50). In the latter case, however, a minimum energy structure may not be adequate, and absorption spectra have to be computed by sampling excited states along QM/MM MD trajectories (8).…”

Section: The Challenge Of Excited States In Biomoleculesmentioning

confidence: 99%

Hybrid Quantum Mechanical/Molecular Mechanical Methods For Studying Energy Transduction in Biomolecular Machines

Kubař

Elstner

Cui

2023

Annu. Rev. Biophys.

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Hybrid quantum mechanical/molecular mechanical (QM/MM) methods have become indispensable tools for the study of biomolecules. In this article, we briefly review the basic methodological details of QM/MM approaches and discuss their applications to various energy transduction problems in biomolecular machines, such as long-range proton transports, fast electron transfers, and mechanochemical coupling. We highlight the particular importance for these applications of balancing computational efficiency and accuracy. Using several recent examples, we illustrate the value and limitations of QM/MM methodologies for both ground and excited states, as well as strategies for calibrating them in specific applications. We conclude with brief comments on several areas that can benefit from further efforts to make QM/MM analyses more quantitative and applicable to increasingly complex biological problems. Expected final online publication date for the Annual Review of Biophysics, Volume 52 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Unravelling the mechanism of glucose binding in a protein-based fluorescence probe: molecular dynamics simulation with a tailor-made charge model

Abstract: Fluorophores linked to the glucose/galactose-binding protein (GGBP) are a promising class of glucose sensors with potential application in medical devices for diabetes patients. Several different fluorophores at different positions in...

Cited by 2 publications

References 60 publications

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

Hybrid Quantum Mechanical/Molecular Mechanical Methods For Studying Energy Transduction in Biomolecular Machines

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