Molecular Dynamics Simulations of the <i>c-kit1</i> Promoter G-Quadruplex: Importance of Electronic Polarization on Stability and Cooperative Ion Binding

Salsbury, Alexa M.; Lemkul, Justin A.

doi:10.1021/acs.jpcb.8b11026

Cited by 38 publications

(87 citation statements)

References 88 publications

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“…Ion occupancy maps were generated as described elsewhere (45)(46)(47). The system volume was divided into discrete, 1-Å 3…”

Section: Ion Sampling Around Gqsmentioning

confidence: 99%

“…Details of the parametrization strategy, functional form, and integration algorithms associated with the Drude FF are reviewed in (42). The Drude FF has successfully modeled duplex DNA (40,41), DNA base flipping (43), ion-DNA interactions (44), DNA GQs (45)(46)(47), and RNA GQs (46), demonstrating its promise for investigations into the dynamics and energetics of GQs, including the c-kit1 GQ studied here.…”

Section: Introductionmentioning

confidence: 99%

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Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

Salsbury

Lemkul

2021

Biophysical Journal

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Nucleic acid-ion interactions are fundamentally important to the physical, energetic, and conformational properties of DNA and RNA. These interactions help fold and stabilize highly ordered secondary and tertiary structures, such as G-quadruplexes (GQs), which are functionally relevant in telomeres, replication initiation sites, and promoter sequences. The c-kit protooncogene encodes for a receptor tyrosine kinase and is linked to gastrointestinal stromal tumors, mast cell disease, and leukemia. This gene contains three unique GQ-forming sequences that have proposed antagonistic effects on gene expression. The dominant GQ, denoted c-kit1, has been shown to decrease expression of c-kit transcripts, making the c-kit1 GQ a promising drug target. Toward disease intervention, more information is needed regarding its conformational dynamics and ion binding properties. Therefore, we performed molecular dynamics simulations of the c-kit1 GQ with K þ , Na þ , Li þ , and mixed salt solutions using the Drude-2017 polarizable force field. We evaluated GQ structure, ion sampling, core energetics, ion dehydration and binding, and ion competition and found that each analysis supported the known GQ-ion specificity trend (K þ > Na þ > Li þ ). We also found that K þ ions coordinate in the tetrad core antiprismatically, whereas Na þ and Li þ align coplanar to guanine tetrads, partially because of their attraction to surrounding water. Further, we showed that K þ occupancy is higher around the c-kit1 GQ and its nucleobases than Na þ and Li þ , which tend to interact with backbone and sugar moieties. Finally, we showed that K þ binding to the c-kit1 GQ is faster and more frequent than Na þ and Li þ . Such descriptions of GQ-ion dynamics suggest the rate of dehydration as the dominant factor for preference of K þ by DNA GQs and provide insight into noncanonical nucleic acids for which little experimental data exist.

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“…Ion occupancy maps were generated as described elsewhere (45)(46)(47). The system volume was divided into discrete, 1-Å 3…”

Section: Ion Sampling Around Gqsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

Salsbury

Lemkul

2021

Biophysical Journal

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“…In contrast, any larger perturbation of the quartets in simulations of GQ structures derived from experiments indicate that an inadequate force field has been used. 42,97 Still, even with appropriate force fields, subtle details of the structures (details of quartet's H-bonds, 29,72 cation distribution, 29 backbone substates 57 and loop conformations 68,69,71 ) may be sampled imperfectly.…”

Section: Force-field Approximations and Their Effect On G-stem Simulamentioning

confidence: 99%

“…These methods magnify the free-energy differences among the substates while the simulation time scale is not sufficient to provide their converged populations. 77 Recent literature data suggest that polarizable force fields could substantially improve the description of ions in GQs, 97 though they may still require a careful calibration and it is not yet clear if they do not introduce other hitherto not identified problems. However, G-stems stabilized by cations are genuine systems for application of the polarizable force fields.…”

Section: Force-field Approximations and Their Effect On G-stem Simulamentioning

confidence: 99%

Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

Islam

Stadlbauer

Vorlı́čková

et al. 2019

Preprint

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G-quadruplexes (GQ) are four-stranded non-canonical DNA and RNA architectures that can be formed by guanine-rich sequences. The stability of GQs increases with the number of G-quartets and three G-quartets generally form stable GQs. However, stability of two-quartet GQs is an open issue. To understand the intrinsic stability of two-quartet GQ stems, we have carried out a expression. 5 Therefore, there is considerable interest in studying and modulating the formation of GQs as a means for controlling gene expression and other cellular processes. 6 GQs are formed by stacking of planar guanine quartets, creating the G-stem. The O6 atoms of all the guanines face to form a central electron-rich channel within the GQ where cations bind and coordinate with the O6 atoms. This coordination is essential for GQ stability. 7 Bases not involved in G-stem belong to bulges, flanking nucleotides or participate in the loops linking the G-strands of the GQs. 3The GQs can be monomolecular, bimolecular or tetramolecular depending on the number of DNA or RNA molecules that form the GQ. 8,9 The topologies of GQs are highly variable as the G-strand orientation can be parallel or antiparallel and based on that GQs can fold into parallel, antiparallel or hybrid topology. 10,11 The guanines in the DNA GQs can adopt syn or anti orientation. 10,12,13 In the RNA GQs, the 2 -hydroxyl group in ribose allows for more interactions with the bases, cations and water molecules thereby increasing their stability, as common in RNA molecules. [14][15][16][17][18][19] It also restricts the orientation of the guanine bases favouring the anti-orientation. 14 Therefore, the majority of the RNA GQs have been observed in the parallel-stranded topology with all bases in the anti-orientation. [15][16][17][18] The loops further add to the diversity as the GQs can have propeller, lateral or diagonal loops. 8,[20][21][22][23][24][25][26][27] The parallel-stranded GQ have propeller (double-chain reversal) loops as they are necessary to orient the following and preceding G-strands in a parallel arrangement. 8 The antiparallel and hybrid GQs can have various combinations of the three loop types. [20][21][22][23][24][25][26][27] The overall GQ topology dictates the loop combination as well as the allowable syn-anti patterns of the guanines. Na + ions tend to coordinate within the plane while K + ions coordinate between the planes of the G-quartets. 28,29 The cation-quadruplex interactions can induce kinetic and equilibrium differences between the different topologies. 28,30,31 Stability of GQs is affected by the number of G-quartets in the stem. 14,[32][33][34] It is commonly accepted that increasing the number of G-quartets usually stabilizes the GQ structure. 12,14,34,35 In DNA, stable GQ structures generally involve three quartets or more, although stable antiparallel two-quartet GQs with loop alignments or stacked triads have also been observed. 21, 36 27 In such GQs, additional interactions formed by the loops or triads above and/or below the G-stems contribut...

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“…38 Its recent modification Drude2017 was claimed that it outperforms CHARMM36 force field in the simulation of GQ. [39][40][41][42] Besides, with induced polarization effect included, Song et al developed polarized nucleic acidspecific charge, namely PNC force field, and obtained a significantly improved description of GQ compared with Amber ff10 force field. 26 The force field, atomic multipole optimized energetics for biomolecular applications (AMOEBA) also incorporates polarization effect.…”

Section: Introductionmentioning

confidence: 99%

Extensive Evaluation of Force Fields for G-Quadruplexes

Li¹,

Zhu

2021

Preprint

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<p><a></a><a></a><a>G-Quadruplexes</a> (GQs), folded by guanine-rich <a></a><a></a><a>nucleic acid</a> <a></a><a></a><a></a><a>sequences</a>, involve in gene expression processes and closely associated with the formation of tumors. So far, GQ has drawn widespread attention for its notable application of serving as potential anti-cancer target. Recently, theoretical studies for GQs have achieved significant progress, most of which are inseparable from molecular dynamics (MD) simulation. As a necessary tool to explore <a></a><a></a><a>dynamics behavior</a> of molecules, MD simulations strictly depend on force field parameters, which is a sticking point to obtain accurate results. Currently, many force fields for nucleic acids have been developed, but none of them have been accepted widely for GQs. In this paper, we selected five popular force fields, which are parmbsc0, parmbsc1, OL15, Drude2017 and AMOEBANUC17, and conducted explicit-solvent MD simulations on two DNA GQs respectively. We evaluated these force fields from many aspects in detail. Meanwhile, we compared conformational energy using quantum chemistry calculations. With the comprehensive evaluation, Drude2017 achieved better description for GQs, which we suggest that using Drude2017 force field should <a></a><a></a><a>be taken into account</a> first when investigating GQs by MD simulation<a></a><a></a><a></a><a></a><a>.</a></p>

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Molecular Dynamics Simulations of the c-kit1 Promoter G-Quadruplex: Importance of Electronic Polarization on Stability and Cooperative Ion Binding

Cited by 38 publications

References 88 publications

Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

Extensive Evaluation of Force Fields for G-Quadruplexes

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