The G‐Triplex DNA

Limongelli, Vittorio; Tito, Stefano De; Cerofolini, Linda; Fragai, Marco; Pagano, Bruno; Trotta, Roberta; Cosconati, Sandro; Marinelli, Luciana; Novellino, Ettore; Bertini, Ivano; Randazzo, Antonio; Luchinat, Claudio; Parrinello, Michele

doi:10.1002/anie.201206522

Cited by 137 publications

(137 citation statements)

References 30 publications

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“…The acceleration of the sampling is made possible by introducing during the simulation a history-dependent bias potential on few degrees of freedom of the system of interest, called collective variables (CVs). This technique has been already successfully used in several fields, like DNA folding (40), ligand/protein binding (41, 42), large-scale protein motion (43, 44), and chemical reactions (45), and it has been proven to be rigorously justified (46). Here, to study the berberine/G4-DNA binding process and compute the ligand/DNA absolute binding free energy, we have used a recent variant of the original method, called funnel-metadynamics (37).…”

Section: Resultsmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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102

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SignificanceA thorough characterization of the binding interaction between a drug and its molecular target is fundamental to successfully lead drug design. We demonstrate that this characterization is also possible using the recently developed method of funnel-metadynamics (FM), here applied to investigate the binding of berberine to DNA G-quadruplex. We computed a quantitatively well-characterized free-energy landscape that allows identifying two low-energy ligand binding modes and the presence of higher energy prebinding states. We validated the accuracy of our calculations by steady-state fluorescence experiments. The good agreement between the theoretical and experimental binding free-energy value demonstrates that FM is a most reliable method to study ligand/DNA interaction.

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Section: Resultsmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…Among the emerging techniques, metadynamics (25) has proven to be very useful in studying long-timescale processes (26,27), particularly in complex ligand/protein binding cases (28)(29)(30). Metadynamics works by adding an external history-dependent potential that acts on few degrees of freedom, named collective variables (CVs).…”

mentioning

confidence: 99%

Funnel metadynamics as accurate binding free-energy method

Limongelli

Bonomi

Parrinello

2013

Proc. Natl. Acad. Sci. U.S.A.

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350

502

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A detailed description of the events ruling ligand/protein interaction and an accurate estimation of the drug affinity to its target is of great help in speeding drug discovery strategies. We have developed a metadynamics-based approach, named funnel metadynamics, that allows the ligand to enhance the sampling of the target binding sites and its solvated states. This method leads to an efficient characterization of the binding free-energy surface and an accurate calculation of the absolute protein-ligand binding free energy. We illustrate our protocol in two systems, benzamidine/ trypsin and SC-558/cyclooxygenase 2. In both cases, the X-ray conformation has been found as the lowest free-energy pose, and the computed protein-ligand binding free energy in good agreement with experiments. Furthermore, funnel metadynamics unveils important information about the binding process, such as the presence of alternative binding modes and the role of waters. The results achieved at an affordable computational cost make funnel metadynamics a valuable method for drug discovery and for dealing with a variety of problems in chemistry, physics, and material science. Studying the molecular interactions between a drug and its target helps in understanding the target functional mechanism and offers the possibility for exogenous control of its physiological activity. In recent years, a vast experimental and computational effort has revealed in ever-more-precise detail the ligand/target recognition mechanism (1, 2). In this context, an accurate estimation of the ligand-binding affinity is in great demand because it would facilitate many steps of the drug discovery pipeline, such as structure-based drug design and lead optimization; this is not, however, a simple task. In fact, an accurate estimation of the binding affinity or, equivalently, the absolute protein-ligand binding free energy, requires an accurate description of the ligand/ protein interactions, their flexibility, and the solvation process. Many methods have been proposed to tackle this problem. For instance, docking protocols are widely used to generate and rank candidate poses based on empirical scoring functions, either physically or statistically based (3-5). These techniques have been proven to be highly efficient in screening a large number of compounds in a short time (6); this, however, at the price of limited accuracy in estimating affinities (7).Alternatively, a variety of methods to describe ligand/protein interactions in a more accurate way at higher computational cost have been proposed. These techniques can be grouped in two categories: (i) endpoint and (ii) pathway methods. The former group is composed of those techniques that sample ligand and protein in unbound and bound states and compute the proteinligand binding free energy by taking the difference between the absolute free energy of these two states. Examples include microscopic linear response approximation (8), linear interaction energy (9, 10), protein dipoles Langevin dipoles (11), as well as mol...

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“…A G-rich sequence with only three G-tracts may form a G-triplex with stacked G-triads, in which a central guanine connects with two other guanines by Hoogsteen-like hydrogen-bonds (Figure 1)78910. The formation of these G-triplexes has been hypothesized111213, and experiments have suggested that they might be intermediates during folding or unfolding of G-quadruplexes91314151617.…”

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confidence: 99%

“…The formation of these G-triplexes has been hypothesized111213, and experiments have suggested that they might be intermediates during folding or unfolding of G-quadruplexes91314151617. Recently, Limongelli et al demonstrated the formation of G-triplexes in the G-rich sequence, 5'-GGTTGGTGTGG-3', using nuclear magnetic resonance (NMR) experiment in a dilute solution78. However, the melting temperature of the observed G-triplex was 33.5°C, suggesting that the structure is not stable at physiological temperatures.…”

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confidence: 99%

Divalent cations and molecular crowding buffers stabilize G-triplex at physiologically relevant temperatures

Jiang

Cui

Zhao

et al. 2015

Sci Rep

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G-triplexes are non-canonical DNA structures formed by G-rich sequences with three G-tracts. Putative G-triplex-forming sequences are expected to be more prevalent than putative G-quadruplex-forming sequences. However, the research on G-triplexes is rare. In this work, the effects of molecular crowding and several physiologically important metal ions on the formation and stability of G-triplexes were examined using a combination of circular dichroism, thermodynamics, optical tweezers and calorimetry techniques. We determined that molecular crowding conditions and cations, such as Na+, K+, Mg2+ and Ca2+, promote the formation of G-triplexes and stabilize these structures. Of these four metal cations, Ca2+ has the strongest stabilizing effect, followed by K+, Mg2+, and Na+ in a decreasing order. The binding of K+ to G-triplexes is accompanied by exothermic heats, and the binding of Ca2+ with G-triplexes is characterized by endothermic heats. G-triplexes formed from two G-triad layers are not stable at physiological temperatures; however, G-triplexes formed from three G-triads exhibit melting temperatures higher than 37°C, especially under the molecular crowding conditions and in the presence of K+ or Ca2+. These observations imply that stable G-triplexes may be formed under physiological conditions.

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The G‐Triplex DNA

Cited by 137 publications

References 30 publications

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Funnel metadynamics as accurate binding free-energy method

Divalent cations and molecular crowding buffers stabilize G-triplex at physiologically relevant temperatures

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