Sequence‐Specific Positions of Water Molecules at the Interface between DNA and Minor Groove Binders

Spitzer, Gudrun M.; Fuchs, Julian E.; Markt, Patrick; Kirchmair, Johannes; Wellenzohn, Bernd; Langer, Thierry; Liedl, Klaus R.

doi:10.1002/cphc.200800647

Cited by 14 publications

(30 citation statements)

References 69 publications

(65 reference statements)

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“…Fluorescence images showed selective staining of the cell nucleus, and remarkable co-localization with Hoechst dye (Figure 6E – H and Supplementary Figure S14E–S14H). Further, cells showed the pattern of black nucleoli, which is a characteristic feature of specific DNA minor groove binders over single-strand DNA and RNAs ( 59 ). Therefore, staining results obtained with live and fixed cells confirmed high cell permeability, efficiency (low staining concentration of 1 μM), and preferential targeting of cell nuclear DNA.…”

Section: Resultsmentioning

confidence: 99%

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

et al. 2015

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In molecular biology, understanding the functional and structural aspects of DNA requires sequence-specific DNA binding probes. Especially, sequence-specific fluorescence probes offer the advantage of real-time monitoring of the conformational and structural reorganization of DNA in living cells. Herein, we designed a new class of D2A (one-donor-two-acceptor) near-infrared (NIR) fluorescence switch-on probe named quinone cyanine–dithiazole (QCy–DT) based on the distinctive internal charge transfer (ICT) process for minor groove recognition of AT-rich DNA. Interestingly, QCy–DT exhibited strong NIR-fluorescence enhancement in the presence of AT-rich DNA compared to GC-rich and single-stranded DNAs. We show sequence-specific minor groove recognition of QCy–DT for DNA containing 5′-AATT-3′ sequence over other variable (A/T)4 sequences and local nucleobase variation study around the 5′-X(AATT)Y-3′ recognition sequence revealed that X = A and Y = T are the most preferable nucleobases. The live cell imaging studies confirmed mammalian cell permeability, low-toxicity and selective staining capacity of nuclear DNA without requiring RNase treatment. Further, Plasmodium falciparum with an AT-rich genome showed specific uptake with a reasonably low IC50 value (<4 µM). The ease of synthesis, large Stokes shift, sequence-specific DNA minor groove recognition with switch-on NIR-fluorescence, photostability and parasite staining with low IC50 make QCy–DT a potential and commercially viable DNA probe.

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Section: Resultsmentioning

confidence: 99%

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

et al. 2015

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“…As such, the hydrating water molecules form an activation barrier for molecular drugs targeting the major and minor grooves of DNA, and essential biological processes such as DNA transcription involving biomolecules binding to DNA displacing the solvation shell. 2 − 5 Consequently, DNA’s hydration shell has been studied extensively with X-ray crystallography, 6 − 9 neutron scattering, 10 NMR spectroscopy, 11 − 13 electronic 14 and vibrational spectroscopy 15 and molecular dynamics (MD) simulations. 16 , 17 X-ray experiments performed at cryogenic temperatures have shown the existence of structural water molecules in particular minor groove sequences, giving notion to the presence of a spine of hydration in the DNA minor groove.…”

Section: Introductionmentioning

confidence: 99%

DNA’s Chiral Spine of Hydration

et al. 2017

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The iconic helical structure of DNA is stabilized by the solvation environment, where a change in the hydration state can lead to dramatic changes to the DNA structure. X-ray diffraction experiments at cryogenic temperatures have shown crystallographic water molecules in the minor groove of DNA, which has led to the notion of a spine of hydration of DNA. Here, chiral nonlinear vibrational spectroscopy of two DNA sequences shows that not only do such structural water molecules exist in solution at ambient conditions but that they form a chiral superstructure: a chiral spine of hydration. This is the first observation of a chiral water superstructure templated by a biomolecule. While the biological relevance of a chiral spine of hydration is unknown, the method provides a direct way to interrogate the properties of the hydration environment of DNA and water in biological settings without the use of labels.

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“…Instead, there is an interfacial water molecule that links the inner facing amidine-NH to T16-O2 (Figure 1) at the floor of the groove (-NH●●●O-H●●●O=T). This water molecule, unlike the other waters that are well known to externally stabilize minor groove complexes 21,22 , is an integral part of a trimer DB2277-DNA-water complex. Both amidines are also stabilized by a dynamic, external, extended water-network in the groove (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Bound Compound, Interfacial Water, and Phenyl Ring Rotation Dynamics of a Compound in the DNA Minor Groove

Harika

Wilson

2018

Biochemistry

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DB2277, a heterocyclic diamidine, is a successful design for mixed base pair (bp) DNA sequence recognition. The compound has a central aza-benzimidazole group that forms two H-bonds with a GC bp that has flanking AT bps. The nuclear magnetic resonance structure of the DB2277-DNA complex with an AAGATA recognition site sequence was determined, and here we report extended molecular dynamics (MD) simulations of the structure. DB2277 has two terminal phenyl-amidine groups, one of which is directly linked to the DB2277 heterocyclic core and the other through a flexible -OCH- group. The flexibly linked phenyl is too far from the minor groove floor to make direct H-bonds but is linked to an AT bp through water-mediated H-bonds. The flexibly linked phenyl-amidine with water-mediated H-bonds to the bases at the floor of the minor groove suggested that it might rotate in time spans accessible in MD. To test this idea, we conducted multimicrosecond MD simulations to determine if these phenyl rotations could be observed for a bound compound. In a 3 μs simulation, highly dynamic torsional motions were observed for the -OCH-linked phenyl but not for the other phenyl. The dynamics periodically reached a level to allow 180° rotation of the phenyl while it was still bound in the minor groove. This is the first observation of rotation of a phenyl bound to DNA, and the results provide mechanistic details about how a rotation can occur as well as how mixed bp recognition can occur for monomer compounds bound to the minor groove.

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Sequence‐Specific Positions of Water Molecules at the Interface between DNA and Minor Groove Binders

Cited by 14 publications

References 69 publications

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

DNA’s Chiral Spine of Hydration

Bound Compound, Interfacial Water, and Phenyl Ring Rotation Dynamics of a Compound in the DNA Minor Groove

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