Modulation of Hoogsteen dynamics on DNA recognition

Xu, Yan; McSally, James; Andricioaei, Ioan; Al‐Hashimi, Hashim M.

doi:10.1038/s41467-018-03516-1

Cited by 56 publications

(92 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The simulated free energy differences and barrier heights are not directly comparable with the experimental results which are estimated based on simple assumption of Boltzmann probability and transition state theory (TST). Still, we obtained the relative free energy of the HG base pair with respect to WC (∆G W C→HG ) to be 4.5 kcal/mol which is within 1 kcal/mol agreement with NMR experiments and microsecond timescale umbrella sampling and meta-dynamics simulations (23,25,26). The positions of the WC and HG minima in χ − Θ space also agree with earlier computational results (25,26).…”

Section: Free Energy Surfaces From Meta-eabfsupporting

confidence: 88%

“…Enhanced sampling simulation: The newly developed meta-eABF method (39) implemented in NAMD 2.12 through the colvars module (55) has been used to obtain the potential of mean force. The glycosidic angle χ and the pseudo-dihedral angle Θ of the A16-T9 base pair were chosen as order parameters following earlier studies (2,23,26,56). The χ angle denotes torsion of the adenine base with respect to the deoxyribose sugar (defined as the dihedral angle between O4 − C1 − N9 − C4), while the Θ angle captures the flip-out motion of adenine, which leads to extra-helical conformations through base pair breaking (26).…”

Section: System Preparation and Equilibrationmentioning

confidence: 99%

“…In the present paper, we perform a computational comparison of the free energy psurface and transition paths of DNA vs RNA WC to HG transitions, seeking to understand the relative stability of the HG state and the factors that modulate the dynamical equilibrium in DNA vs RNA.The first report (2) of the NMR measured WC-HG dynamic equilibrium also included our preliminary work on searching pathways of conformational transition using a biased molecular dynamics simulation. Further computational work from our group and others (12,(23)(24)(25)(26) have since uncovered several other pieces of information, including energetic details, transition pathways and kinetics of the transition between WC and HG base pairs in naked A-T rich DNA helical duplexes. The paths predicted in our initial study were also recently sampled by Vreede et al(27), who have calculated the rate constants of back and forth transitions between WC and HG base pairs using Transition Path Sampling (TPS) (28).Experimental estimates put the WC-HG transition in DNA on a timescale of 50-250 ms (2).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Ray

Andricioaei

2020

Preprint

View full text Add to dashboard Cite

Genetic information is encoded in the DNA double helix which, in its physiological milieu, is characterized by the iconical Watson-Crick nucleobase pairing. Recent NMR relaxation experiments revealed the transient presence of an alternative, Hoogsteen base pairing pattern in naked DNA duplexes and estimated its relative stability and lifetime. In contrast, HG transitions in RNA were not observed. Understanding Hoogsteen (HG) base pairing is important because the underlying "breathing" can modulate significantly DNA/RNA recognition by proteins. However, a detailed mechanistic insight into the transition pathways and kinetics is still missing. We performed enhanced sampling simulation (with combined metadynamics and adaptive force bias method) and Markov State modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both naked B-DNA and A-RNA duplexes. The Markov state model constructed from our unbiased MD simulation data revealed previously unknown complex extra-helical intermediates in this seemingly simple process of base pair conformation switching in B-DNA. Extending our calculation to A-RNA, for which HG base pair is not observed experimentally, resulted in relatively unstable single hydrogen bonded distorted Hoogsteen like base pair. Unlike B-DNA the transition pathway primarily involved base paired and intra-helical intermediates with transition timescales much higher than that of B-DNA. The seemingly obvious flip-over reaction coordinate, i.e., the glycosidic torsion angle is unable to resolve the intermediates; so a multidimensional picture, involving backbone dihedral angles and distance between atoms participating in hydrogen bonds, is required to gain insight into the molecular mechanism. SIGNIFICANCE Formation of unconventional Hoogsteen (HG) base pairing is an important problem in DNA biophysics owing to its key role in facilitating the binding of DNA repairing enzymes, proteins and drugs to damaged DNA. X-ray crystallography and NMR relaxation experiments revealed the presence of HG base pair in naked DNA duplex and protein-DNA complex but no HG base pair was observed in RNA. Molecular dynamics simulations could reproduce the experimental free energy cost of HG base pairing in DNA although a detailed mechanistic insight is still missing. We performed enhanced sampling simulation and Markov state modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both B-DNA and A-RNA.Manuscript submitted to Biophysical Journal 1 D. Ray and I. Andricioaei duplex DNA beyond what can be achieved by Watson-Crick base-pairing alone. For example, HG base pairs are recognized by DNA repairing enzymes resulting in selective binding in the damaged regions of DNA, rich in syn-anti configuration over the anti-anti WC base pair rich normal DNA. Thus, apart from providing structural integrity to the damaged and deformed DNA, HG base pairs assist in the DNA repair mechanism (13).A...

show abstract

Section: Free Energy Surfaces From Meta-eabfsupporting

confidence: 88%

Section: System Preparation and Equilibrationmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Ray

Andricioaei

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…an antibiotic with anti-tumor activity (51,52) that binds to CpG steps (CG) in dsDNA. Prior studies have shown that when two echinomycin molecules (or its close analog triostin A) bind to DNA sequences containing a TpA step sandwiched between two CpG bindingsites (d(CGTACG)), the TpA step forms two tandem A-T Hoogsteen bps (25,(53)(54)(55)(56)(57).…”

Section: Echinomycin-dna Complexes As Models For Watson-crick and Hoomentioning

confidence: 99%

Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage

Manghrani

Liu

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

As the Watson-Crick faces of nucleobases are protected in double-stranded DNA (dsDNA), it is commonly assumed that deleterious alkylation damage to the Watson-Crick faces of nucleobases predominantly occurs when DNA becomes single-stranded during replication and transcription. However, damage to the Watson-Crick faces of nucleobases has been reported in dsDNA in vitro through mechanisms that are not understood. In addition, the extent of protection from methylation damage conferred by dsDNA relative to single-stranded DNA (ssDNA) has not been quantified. Watson-Crick base-pairs in dsDNA exist in dynamic equilibrium with Hoogsteen base-pairs that expose the Watson-Crick faces of purine nucleobases to solvent. Whether this can influence the damage susceptibility of dsDNA remains unknown. Using dot-blot and primer extension assays, we measured the susceptibility of adenine-N1 to methylation by dimethyl sulfate (DMS) when in an A-T Watson-Crick versus Hoogsteen conformation. Relative to unpaired adenines in a bulge, Watson-Crick A-T base-pairs in dsDNA only conferred ~130-fold protection against adenine-N1 methylation and this protection was reduced to ~40-fold for A(syn)-T Hoogsteen base-pairs embedded in a DNA-drug complex. Our results indicate that Watson-Crick faces of nucleobases are accessible to alkylating agents in canonical dsDNA and that Hoogsteen base-pairs increase this accessibility. Given the higher abundance of dsDNA relative to ssDNA, these results suggest that dsDNA could be a substantial source of cytotoxic damage. The work establishes DMS probing as a method for characterizing A(syn)-T Hoogsteen base pairs in vitro and also lays the foundation for a sequencing approach to map A(syn)-T Hoogsteen and unpaired adenines genome-wide in vivo.

show abstract

“…[2][3][4] Those observations led to a suggestion that the WC double helixes might also code for Hoogsteen base-pairing intrinsically, which offers a way of expanding the genetic information embedded in DNA structures beyond the capacity of WC base-pairing. However, recent NMR studies have observed transient sequence-specific base-pairing other than the WC type, which occurred inside canonical DNA double helixes.…”

mentioning

confidence: 99%

Theoretical Comparison of the Stabilities of Hoogsteen and Watson–Crick Conformations for Proton‐bound Base‐pairing of Nucleic Acid Bases and Nucleosides in the Gas Phase

Han

2019

Bulletin Korean Chem Soc

View full text Add to dashboard Cite

Since the discovery of the Watson-Crick (WC) doublehelical structures of DNA molecules, 1 the specific binding involved in G-C (guanine-cytosine) and A-T (adeninethymine) base-pairing has been known to play a key role in the inheritance of genetic information. However, recent NMR studies have observed transient sequence-specific base-pairing other than the WC type, which occurred inside canonical DNA double helixes. 2-4 Those observations led to a suggestion that the WC double helixes might also code for Hoogsteen base-pairing intrinsically, which offers a way of expanding the genetic information embedded in DNA structures beyond the capacity of WC base-pairing.In fact, it is hydrogen bonding that directs the specific base-pairing between complementary nucleic acid bases. In particular, base-pairing in proton-bound Hoogsteen base pairs of C and G, [C:G:H] + , involves two hydrogen bonds of which one is ionic. 5 The ionic hydrogen bond, which is formed by the extra proton obtained by protonation that bridges between the basic sites of two nucleic acid bases, possesses quite a different property from that of neutral hydrogen bonds. Due to the electrostatic interaction, the ionic hydrogen bonding offers a stronger interaction than neutral hydrogen bonding. 6 In addition, unlike neutral hydrogen bonding, it possesses a very low energy barrier for proton transfer along the ionic hydrogen bond. 5,7,8 The mobile nature of the attached proton also causes intriguing anomalous behaviors in the dissociation of proton-bound base pairs by altering dissociation pathways, leading to the generation of isomeric fragments of proton-transferred products. 9-11 On the other hand, the attachment of a proton to WC base pairs is also known to significantly strengthen neutral hydrogen bonds participating in WC basepairing. 12,13 The investigation of proton-bound base pairs in the gas phase offers a model system to deepen our understanding of base-pairing interactions at the molecular level, in which protonation is deeply involved. For experimental approaches, (IRMPD) spectroscopy 11,14,15 and energyresolved collision-induced dissociation (ER-CID) experiments 10,16,17 in combination with quantum chemical calculations have yielded accurate elucidation of the structures and base-pairing energies of proton-bound dimers of nucleic acid bases. Although proton-bound base pairs produced by ionic hydrogen bonding, such as proton-bound C dimers, have been extensively investigated, the protonbound Hoogsteen base pairs, [C:G:H] + , have been studied only recently. 10,11,18 In an extensive exploration of the conformations of [C:G:H] + complexes, proton-bound Hoogsteen conformations were predicted to be the most stable, and they were far more stable than protonated WC base pairs. 18 Interestingly, however, a recent IRMPD study, which investigated [C:G:H] + complexes for the first time in the gas phase, observed the co-existence of both conformers, proton-bound Hoogsteen and WC base pairs, which showed a pH-dependence in relative population. 11 Despite...

show abstract

Modulation of Hoogsteen dynamics on DNA recognition

Cited by 56 publications

References 73 publications

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA

Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage

Theoretical Comparison of the Stabilities of Hoogsteen and Watson–Crick Conformations for Proton‐bound Base‐pairing of Nucleic Acid Bases and Nucleosides in the Gas Phase

Contact Info

Product

Resources

About