Importance of base-pair opening for mismatch recognition

Bouchal, Tomáš; Durník, Ivo; Illík, Viktor; Réblová, Kamila; Kulhánek, Petr

doi:10.1093/nar/gkaa896

Cited by 11 publications

(18 citation statements)

References 74 publications

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“…Free energies are reported with confidence intervals provided at three standard deviations (99.7% confidence level). More details on the procedure are provided in ( 55 ).…”

Section: Methodsmentioning

confidence: 99%

c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry

Peterková

Durník

Marek

et al. 2021

Nucleic Acids Research

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Several sequences forming G-quadruplex are highly conserved in regulatory regions of genomes of different organisms and affect various biological processes like gene expression. Diverse G-quadruplex properties can be modulated via their interaction with small polyaromatic molecules such as pyrene. To investigate how pyrene interacts with G-rich DNAs, we incorporated deoxyuridine nucleotide(s) with a covalently attached pyrene moiety (Upy) into a model system that forms parallel G-quadruplex structures. We individually substituted terminal positions and positions in the pentaloop of the c-kit2 sequence originating from the KIT proto-oncogene with Upy and performed a detailed NMR structural study accompanied with molecular dynamic simulations. Our results showed that incorporation into the pentaloop leads to structural polymorphism and in some cases also thermal destabilization. In contrast, terminal positions were found to cause a substantial thermodynamic stabilization while preserving topology of the parent c-kit2 G-quadruplex. Thermodynamic stabilization results from π–π stacking between the polyaromatic core of the pyrene moiety and guanine nucleotides of outer G-quartets. Thanks to the prevalent overall conformation, our structures mimic the G-quadruplex found in human KIT proto-oncogene and could potentially have antiproliferative effects on cancer cells.

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“…Free energies are reported with confidence intervals provided at three standard deviations (99.7% confidence level). More details on the procedure are provided in ( 55 ).…”

Section: Methodsmentioning

confidence: 99%

c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry

Peterková

Durník

Marek

et al. 2021

Nucleic Acids Research

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“…However, calculating roll and especially its gradient with respect to Cartesian coordinates of atoms, needed in biased MD simulations, is a cumbersome task. Therefore, several simplified approaches appeared in the previous studies, which avoided fitting standard reference frames to nucleobases and used dihedral angles instead. ,, To avoid any possible undesired effects of such approaches and provide a clear comparison with our previous work, we decided to avoid such simplification. Therefore, we implemented all six base-pair step parameters, including their gradients into PMFLib, fully compatible with 3DNA ,, (Figure S7).…”

Section: Results and Discussionmentioning

confidence: 99%

“…DNA was neutralized with 28 sodium cations, resulting in c (Na + ) ≈ 195 mM. Usage of physiological NaCl solution was shown to provide a similar outcome . The temperature and pressure were kept at 300 K and 100 kPa, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Bending of Canonical and G/T Mismatched DNAs

Bouchal

Durník

Kulhánek

2021

J. Chem. Inf. Model.

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Mismatched base pairs alter the flexibility and intrinsic curvature of DNA. The role of such DNA features is not fully understood in the mismatch repair pathway. MutS/DNA complexes exhibit DNA bending, PHE intercalation, and changes of base-pair parameters near the mismatch. Recently, we have shown that base-pair opening in the absence of MutS can discriminate mismatches from canonical base pairs better than DNA bending. However, DNA bending in the absence of MutS was found to be rather challenging to describe correctly. Here, we present a computational study on the DNA bending of canonical and G/T mismatched DNAs. Five types of geometric parameters covering template-based bending toward the experimental DNA structure, global, and local geometry parameters were employed in biased molecular dynamics in the absence of MutS. None of these parameters showed higher discrimination than the base-pair opening. Only roll could induce a sharply localized bending of DNA as observed in the experimental MutS/DNA structure. Further, we demonstrated that the intercalation of benzene mimicking PHE decreases the energetic cost of DNA bending without any effect on mismatch discrimination.

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“…[29][30][31][32][33] To obtain sufficient data for post-processing analyses, the approximated mean-field molecular mechanics (MM) force fields are widely employed in molecular dynamics (MD) simulations of biomolecular systems. [34][35][36][37][38][39] In this work, we present a comprehensive computational investigation of the host-guest interaction in CB8-drugs systems. Seven commonly used and abused drugs including Metamfetamine, Fentanyl, Cocaine, 4 / 80 Phencyclidine, Ketamine, Morphine, and Hydromorphone are considered.…”

Section: Introductionmentioning

confidence: 99%

A General Picture of Cucurbit[8]uril Host-Guest Binding

Sun

Huai

et al. 2021

Preprint

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Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modelling. The barrel-shaped supra-molecular container Cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of 7 commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Extensive sampling of the configurational space of these host-guest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated in detail. Iterative refitting of the atomic charges suggests significant conformation-dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes (e.g., bracelet-like guest conformations and crescent free energy landscapes). Thus, understandings obtained from static calculations based on a single or several structures are limited for these host-guest interactions. The investigation protocol provides useful guidelines for studying host-guest binding, and the insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for elucidating the binding mechanism of other host-guest complexes.

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Importance of base-pair opening for mismatch recognition

Cited by 11 publications

References 74 publications

c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry

c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry

Bending of Canonical and G/T Mismatched DNAs

A General Picture of Cucurbit[8]uril Host-Guest Binding

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