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Hofmeister series and ionic effects of alkali metal ionson DNA conformation transition in normal and lesspolarised water solventJing Wenab, Xin Shenab, Hao Shenab & Feng-Shou Zhangabc

a The Key Laboratory of Beam Technology and Material Modification of the Ministry ofEducation, College of Nuclear Science and Technology, Beijing Normal University, Beijing,Chinab Beijing Radiation Center, Beijing, Chinac Center of Theoretical Nuclear Physics, National Laboratory of the Heavy Ion Accelerator ofLanzhou, Lanzhou, ChinaPublished online: 08 May 2014.

To cite this article: Jing Wen, Xin Shen, Hao Shen & Feng-Shou Zhang (2014) Hofmeister series and ionic effects of alkalimetal ions on DNA conformation transition in normal and less polarised water solvent, Molecular Physics: An InternationalJournal at the Interface Between Chemistry and Physics, 112:20, 2707-2719, DOI: 10.1080/00268976.2014.906674

To link to this article: http://dx.doi.org/10.1080/00268976.2014.906674

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Molecular Physics, 2014Vol. 112, No. 20, 2707–2719, http://dx.doi.org/10.1080/00268976.2014.906674

RESEARCH ARTICLE

Hofmeister series and ionic effects of alkali metal ions on DNA conformation transitionin normal and less polarised water solvent

Jing Wena,b, Xin Shena,b, Hao Shena,b and Feng-Shou Zhanga,b,c,∗

aThe Key Laboratory of Beam Technology and Material Modification of the Ministry of Education, College of Nuclear Scienceand Technology, Beijing Normal University, Beijing, China; bBeijing Radiation Center, Beijing, China; cCenter of Theoretical

Nuclear Physics, National Laboratory of the Heavy Ion Accelerator of Lanzhou, Lanzhou, China

(Received 15 January 2014; accepted 17 March 2014)

Normal and less polarised water models are used as the solvent to investigate Hofmeister effects and alkali metal ionic effectson dodecamer d(CGCGAATTCGCG) B-DNA with atomic dynamics simulations. As normal water solvent is replaced byless polarised water, the Hofmeister series of alkali metal ions is changed from Li+ > Na+ � K+ � Cs+ � Rb+ to Li+

> Na+ > K+ > Rb+ > Cs+ . In less polarised water, DNA experiences the B→A conformational transition for the lighteralkali metal counterions (Li+ , Na+ and K+ ). However, it keeps B form for the heavier ions (Rb+ and Cs+ ). We find thatthe underlying cause of the conformation transition for these alkali metal ions except K+ is the competition between watermolecules and counterions coupling to the free oxygen atoms of the phosphate groups. For K+ ions, the ‘economics’ ofphosphate hydration and ‘spine of hydration’ are both concerned with the DNA helixes changing.

Keywords: Hofmeister effect; ionic effects; molecular liquids; less polarised solvent; DNA

1. Introduction

Hofmeister found that ions have various effects on pro-tein precipitation, unfolding and surface tension in the later1880s [1]. It is intriguing that elements of the Hofmeis-ter series are in accord with effects of these in receptorsand cell signalling [2–6]. The effects follow the order foranions, sulphate > hydrogen > phosphate > acetate > cit-rate > chloride > nitrate > chlorate > iodide > perchlorate> thiocyanate; and for cations, ammonium > potassium >

sodium > lithium > magnesium > calcium > guanidinium[2]. Another Hofmeister series for cations is (CH3)4N+ >

(CH3)2+ > NH3 + > NH4

+ > K+ > Na+ > Cs+ >

Li+ > Mg2 + > Ca2 + > Ba2 + [7]. There are many rea-sons for the influences that were proposed over the years.The commonly concerned factor suggested the origin ofHofmeister effects as the interactions of salts with solventmolecules and dissolved molecules [8,9]. Still a study [10]showed that the electrostatic approach represents a unify-ing thread. For the Hofmeister effects on the spectra of OHvibrations in water, the effects are due to the electric fieldsof the ions acting on neighbouring molecules. Meanwhile,electrostatic potential energy decays less rapidly with dis-tance than with the field strength, meaning that the Hofmeis-ter series does not concern the long-range effects on bulkwater structure [11].

The Hofmeister salts can affect DNA helix formation[4,5]. As we all know, the unique double-helical DNA struc-

∗Corresponding author. Email: fszhang@bnu.edu.cn

ture with highly charged phosphate backbone contains stor-ing, duplication, realisation and transcription of the geneticinformation, and still has broad prospects in the applicationof supramolecular chemistry and nano-biological technol-ogy of DNA devices [12–15]. For the virtue of the back-bones, DNA is involved in strong electrostatic interactionsand most of the studies focus on these electrostatic interac-tions, especially for the dynamics and structures research onB-DNA [16–21]. We have known much about B-form DNAfrom the structure of the so-called Dickerson–Drew do-decamer (DDD) CGCGAATTCGCG, the crystal structurewhich provides the first detailed image of a right-handedDNA double helix [22]. Some studies based on DDD areinterdependence of base sequence with backbone flexibil-ity, solvation, bending and bend ability, drugs and proteins,and the effects of packing forces [23–28]. So far, the mostaddressed issues focus on the conformation transitions andthe effects of metal cations in the process of folding andcatalysis of nucleic acids [29–31].

The metal cations (most of them are alkali metalions) or protein–DNA complexes neutralise the electro-static force of DNA in aqueous solution [32,33]. Manystudies with experiment methods (X-ray crystallography,nuclear magnetic resonance (NMR) and fluorescent tech-niques) and the all-atom molecular dynamics simula-tions try to address the mechanisms and dynamics onhow metal ions influence the DNA and to modify the

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2708 J. Wen et al.

electrostatic interactions in detail [34–39] since Younget al. [40] proposed that the strongly electronegative pocketsin DDD harbour Na+ ions. K+ ions reside in the cytoplasmof practically all living cells and Cheng et al. [41] foundthat the relationship of DNA with K+ is much closer thanthat with Na+ . Heavier alkali metal ions (Rb+ and Cs+ )prefer to bind in the groove of DNA. With 1.2 A structureof Rb+ –DDD duplex, one Rb+ replaces the inner spinewater and binds to O2 atoms of residues T8 and T20. ThusRb+ ions are localised at the central ApT step of the AATTduplex and prefer replacing the central water of the innerspine [31]. As regards to Cs+ , a single-crystal diffractionstudy of the Cs+ ions on DDD appears to turn out thatCs+ penetration of the minor groove [29]. In some con-ditions, the behaviours of alkali metal ions are similar toalkali earth metal ions. A study [42] found that Na+ ionsof the cross-linked AATT duplex has essentially the samestructure as Mg2 + ions of the native duplex while noneis found deep inside the minor groove. Replacing Mg2 +

by Ca2 + resulted in growth of the rhombohedral crystalformed with novel interactions between the ends of neigh-bouring duplexes [43].

DDD dodecamer is a flexible and polymorphic structurewith conformation changing as a response to the presenceof ligands, variations of the temperature or modifications ofthe solvent [39,44,45]. Conformational transitions of DNA,like B ↔A form, always concern the screening of repulsionbetween negatively charged phosphate groups or the ‘eco-nomics’ of minor groove spine of hydration [45,46]. Bind-ing of DNA-regulatory proteins requires dramatic changesin the structure of nucleic acids. Noy et al. [47] showed thatthe presence of large amounts of ethanol induces a strongchange in the B/A conformational equilibrium. Vargasonet al. [48] described the details of each step in the con-version of B to A-DNA at the atomic level and placed theintermediates for most DNA sequences in the context of acommon pathway. Moradi et al. [49] found that the B toZ-DNA transition in absence of other molecular partnerscan encompass more than one mechanism of comparablefree energy, and is therefore better described in terms of areaction path ensemble. The ionic atmosphere around do-decamer is also affected by these conformation transitions,and vice versa. Cheatham III et al. [50] demonstrated thatB-DNA is stabilised by extensive hydration and hydratedcounterions in the minor groove, anchoring the two strandswith the order of Na+ < K+ < Cs+ . A-DNA is stabilisedby major groove hydration and ion association, and also byion-mediated inter-helical bonds across the major groovesand between duplexes (Na+ > K+ > Cs+ ).

For liquid water, there are many important and unusualproperties, which ultimately depend on the electronic andnuclear structure of individual molecules [51]. The prop-erties of DNA influenced by solvent can be attributed tovarious physical factors of water such as intermolecularforces, tetrahedral network, hydrogen bond strengths and so

forth. For classical simulation methods, one can investigatethe effects by changing the potential parameters of waterto understand the microscopic origin of different phenom-ena [52,53]. Lynden-Bell and Debenedetti [54] performedsimulations of a number of highly distorted water modelsand investigated the properties of these ‘not-water’ sol-vent. They modified the potential parameters (the chargeon oxygen and hydrogen atoms or Lennard-Jones term) ofsimple point charged (SPC) water models and indicatedthat the water evolves from tetrahedral water-like structureto spherically symmetric Lennard-Jones-like structure asthe weight of the Lennard-Jones component increases (orelectrostatic components decrease). Namely, revising thecharges can reduce the extent of structure in the first shell,and get an organic-like liquid, which can be used to in-vestigate DNA in ‘not-water’ solvent environment withoutadding methanol, ethanol or other organic liquids. Our ear-lier letter [45] comments the DNA conformation transitionfrom B to A form as the polarity of SPC solvent moleculeschanges from overpolarised to less polarised.

In this paper, the simulation of DNA conformation tran-sitions in normal and less polarised solvent environmentswith five different alkali metal ions (Li+ , Na+ , K+ , Rb+ ,Cs+ ) has been conducted to study the Hofmeister seriesof these ions and ionic effects on DNA. There still aresome unclear problems concerning the Hofmeister effectson DNA under less polarised solvent. The Hofmeister se-ries of alkali metal ions with DNA is difficult to order innormal water solvent [2,4,7], is it similar in less polarisedsolvent? If there are significant differences, what are they?As remarked in our previous work [45], Na+ ions breakthe hydration shell around the phosphate groups, and inter-act with the negative phosphate oxygen atoms. However,the competition between ions and water in the grooves wasignored. If structure changes, are they just related with the‘economics’ of phosphate hydration or still correlated withthe ‘spine of hydration’? Different ions interact with DNAat different sites and these locating sites may influence theconformation of DNA. When the ions are added into theless polarised solvent, does the DNA conformation transi-tion happen in different ‘organic’ solvents? We try to catchon the mechanisms behind structure changing. The exactbinding sites in the vicinity of DNA are provided at atomicscales by microscope images (e.g. spatial distribution func-tions (SDFs)). The distinct ion–DNA interaction strength,the influence order of ions with the DNA and the behavioursof ions residing at the grooves are presented by the radialdistribution functions (RDFs) and occupancies.

After the Introduction section, we explain the modelof solvent molecule, the DNA segment and ions, and thesimulation methods in Section 2. The phenomena aboutDNA structure change, Hofmeister effects and the distri-bution of ions around DNA are shown and the underlyingcauses of these phenomena are discussed in Section 3. Theconclusion is presented at the end of the paper.

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2. Method and computational details

The intermolecular energy consists of two parts: E = Elj +Ec, where Elj is the Lennard-Jones interaction and Ec is theelectrostatic interaction. They are expressed as

Elj = 4εij

[(σij

rij

)12

−(

σij

rij

)6]

, (1)

Ec = qiqj

4πε0rij

, (2)

where ε0 is the vacuum permittivity and rij presents thedistance between two atoms. By modifying the ratio of Ec

to Elj (the ratio of the tetrahedral part of the intermolecu-lar potential to its spherical symmetric part) [54], we canchange the nature of water. In this paper, the atom chargesof water molecule are scaled by a factor λ and the electro-static term is scaled by λ2: E = Elj + λ2Ec. As the weight-ing of the magnitudes of the atomic charges, λ, decreases,the solvent molecules are less polarised and their hydro-gen bonding ability is decreased. The interactions becomemore isotropic and the liquid changes continuously fromwater-like to Lennard-Jones-like.

The solvent is derived from the widely used flexi-ble SPC water molecule model [55]. The flexibility ofSPC model is considered with a Morse type of potentialfor its covalent bonds [55]: Vbond = D(1 − exp(−ρ(r −req))). The NMR structure of a synthetic B form duplexd(CGCGAATTCGCG) named 171d is chosen from ProteinData Bank [56] as the starting structure in each simulation.The 171d duplex is extensively studied because of its bi-ological importance. It contains the recognition site of theEcoRI restriction enzyme and is frequently used in gene re-combination techniques. The cation force field parametersare presented in Table 1 [57], where ε and σ are Lennard-Jones parameters. There are some studies focusing on theionic effects around DNA and the DNA structure [58–61]using ion force field of Heinzinger [57].

Many force fields have been studied before [62,63]based on the Amber force field developed by Cornell et al.[64]. In our simulations, the force field of Cornell et al. [64]with Amber 94 parameters, including hydrogen bonds be-tween base pairs, is implemented for their special accuracyin reflecting the effects of water activity. The main problemappearing upon the use of Amber 94/99 force field in theprevious studies [65] (associated references they cited) isthe overpopulation of α/γ backbone in long (>10 ns) simu-

Table 1. The force field parameters of alkali metal ions.

Li+ Na+ K+ Rb+ Cs+

σ /A 2.37 2.73 3.36 3.57 3.92ε/kJ/mol 0.149 0.358 0.568 1.602 2.132

lations. The accumulation of ‘non-canonical’ α/γ backbonetorsion angles addresses our concerns for the simulations ofDNA conformation transitions in our previous work [45].However, the Amber 94/99 force field is still used for thestudies of ion–DNA interaction and DNA–DNA interac-tions now with the simulation longer than 10 ns [66,67].Meanwhile, the structure of minor groove is not influencedgreatly by different force fields (see Table 4 in [65]). Basedon that, we choose Amber 94 force field to study the com-petition of ions and ion–DNA interactions.

The package we use to perform molecular dynamic sim-ulations is M.DynaMix, which is developed for simulationsof arbitrary mixtures of molecules and macromolecules insolutions [68,69]. The double time-step algorithm by Tuck-erman et al. [70] is implemented and short time step is 0.2fs for the fast nearest short-range (within 5 A) interactions,while the long time step for those more slowly fluctuatinginteractions is 2.0 fs. The cut-off for long-rang interactionRcut is 14 A and the Ewald method is adopted to treat theelectrostatic interactions with screening parameter α takenas α = 3/Rcut and the reciprocal space cut-off determined[71] by exp(−π2k2

max/α2) = exp(−9).

There are one 171d DNA segment, 22 alkali metal coun-terions and (1) 5000 normal solvent molecules or (2) 5000modified solvent molecules with λ = 0.6 (it was demon-strated as a charge scaling changing the 171d from B to Aform with Na+ ) in each periodic rectangular cell (53 ×53 × 56 A3 at 298 K, big enough to ensure the DNA doesnot interact with its periodic images). The systems withmodified and normal SPC solvent are abbreviated with X06and X (X is the name of alkali metal ions in solution), re-spectively. At the beginning, DNA is fixed in the box centrealong Z direction, and a 100 ps NVT simulation is per-formed to allow solvent molecules and ions to form theouter shells around DNA obtaining an initial balance. Afterthe 1 ns NVT equilibrium of the solvent and ions around thereleased DNA, the product simulations of 40 ns are carriedout for statistical analyses.

Structure parameters describing the global, backbone,local base pair and groove characters of DNA are analysedby the program Curves [72]. A local or base pair coordinateis set to quantify inter-base or intra-base parameters in aright-handed orthogonal axial set. Sugar pucker phase angle(Phi) is a basic characteristic to distinguish A and B form.X displacement (Xdp) describes the displacement of a basepair along the X direction (the direction of the short axis ofthe base pair) of the base pair axis. Slide (Dy) is relativetranslation along the y axis between two successive basepairs in an overall helix axis. Inclination (Inc) is defined asdihedral angle between the base pairs and the plane withthe initial x and y axes [73]. The width (MW for majorgroove and mW for minor groove) and depth (MD for majorgroove and mD for minor groove) of the groove are definedin [66]. All of these parameters are analysed continually forthe precise values in our simulations.

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3. Results and discussion

3.1. Properties of liquid water

The solvent environments will have different effects onthe structure of DNA. Water molecule has distinct polar-ity, which is determined by the atom charges. The atomcharges of water molecule are scaled by a factor S, herethe S is defined as the atom charge ratio between modelwater molecular and the SPC water molecular. One canget five kinds of solvent environments ranging from lesspolarised to overpolarised by modifying the value of S as0.6, 0.7, 0.8, 1.0, 1.2, respectively. In our previous workwe had calculated the tetrahedral parameters of the five dif-ferent solvents and proposed that the local arrangement ofthe solvent molecules changes from structureless randomorientation to evident tetrahedral structure. The potentialcurves of line hydrogen bond between two water moleculesare given in Figure 1. The lowest points of the curves areassumed as the hydrogen bonding strength. It can be seenthat the strength of hydrogen bond is only 0.25 times that ofthe natural water, while it increases to 1.66 times when S is1.2. It can be concluded that in less polar solvent hydrogenbond is weaker, it is strengthened with the polarity of waterincreased. The strength of hydrogen bond influences thelocal structure order of water and the local structure orderis sensitive to the strength of dipole interaction.

3.2. Hofmeister series in normal solvent

In order to study the Hofmeister effects of alkali metalions on DNA in normal water, the RDFs of cations withfree negative oxygens on phosphate are shown in Figure 2.Hofmeister ions are divided as water structure breakers

Figure 1. Potential curves of the solvent dimers with linear hy-drogen bond, the inset is the strength of H bonds.

Figure 2. Radial distribution functions (RDFs) of Li+ , Na+ ,K+ , Rb+ and Cs+ around oxygen atoms of the phosphate groupson DNA backbones in normal solvent.

(‘chaotrope’), destabilising, stabilising and structure mak-ers (‘kosmotropes’) [7]. Hofmeister effects are attributedto the ‘ordering’ or ‘disordering’ of bulk water structureaffected by the particular ions [74]. It can be seen that thefirst maximum of g(r)Li is the biggest, reaching 14.4. Theheights of other peaks are similar, ranging from 7.8 to 9.3,just 3.4, much higher the first peak of g(r) is, more stronglythe cations contact with the free phosphate oxygen atoms ofthe DNA. These strong interactions between ions and phos-phate group disturb the structure of water molecules aroundthe DNA. It seems that different ion distributions (accumu-lation and exclusion) near the surface of bio-molecules areresponsible for the Hofmeister salt effect on a very widerange of aqueous processes [75].

The Hofmeister effect also reflects the interaction be-tween ions and water, which is fairly independent of theion-perturbing molecule interaction [76]. It can be seenfrom Figure 3 that the strength of interaction between ions

Figure 3. Radial distribution functions (RDFs) of these five ionswith solvent molecules.

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Molecular Physics 2711

Figure 4. Spatial distribution functions (SDFs) of Li+ (black) ((a),(f)), Na+ (orange) ((b),(g)), K+ (dark grey) ((c),(h)), Rb+ (light blue)((d),(i)) and Cs+ (dark blue) ((e),(j)) around averaged DNA structures during the last 20 ns in less polarised solvent. The side stereo viewsare presented along the DNA helix axis with the minor groove at the upper half and the major groove at the lower half. SDFs of ions aredrawn for densities >10 particles/nm3.

and water molecules decreases monotonically as the radiusof ions increases with the highest first peak of g(r)Li reach-ing 9.1 while the lowest first peak of g(r)Cs being just 3.2.With these two rules of Hofmeister series, it seems that theHofmeister effect of alkali metal ions from ‘chaotrope’ to‘kosmotropes’ is ordered as Li+ > Na+ � K+ � Cs+ �Rb+ in normal water. The difference between different al-kali metal ions is quite small and it is impossible to arrangethese ions in a specific order in normal water. The formerstudy concluded these behaviours of Hofmeister salts onDNA as the proportion of polar nitrogen and oxygen andhydrocarbon surface of bio-molecules [4]. The observedHofmeister order of small peptides is due to the hydro-carbon surface that reaches 75%. However, the Hofmeisterorder is hard to be obtained on DNA for the hydrocarbonsurface being just 35%.

3.3. Hofmeister effects in less polarised solvent

The Hofmeister effects of alkali metal ions in the less po-lar water solvent are more complex [76]. Karlstrom [76]studied the Hofmeister effects on ions with small non-polarmolecules in highly polarised solvent and found the effectsare linked to the ions and the polarity of solvent. Here thealkali metal ions are investigated with hydrophilic DNAmolecule in less polarised solvent to obtain a proper theo-retical description of the Hofmeister effects. These ions alsoinfluence the structure of DNA, the mechanism of ionic andHofmeister effects will be explained together in this section.

Stereo views of the averaged DNA structures and SDFsof the ions around the DNA during the last 20 ns simu-lations are presented in Figure 4. Here we just give theDNA conformation transition in solvent with λ = 0.6 forthe slight changing of DNA structure in normal water. Thedistinct difference can be seen that Li+ ions totally changethe DNA from B to A form (Figure 4(a) and 4(f)). The basepairs are inclined with large angles and a hole is clear inthe centre of DNA, close to the characteristic of A form.Li+ ions evenly distribute around backbones and no ionslocate in the grooves. As for Na+ ions (Figure 4(b) and4(g)) and K+ ions (Figure 4(c) and 4(h)), the conformationis similar to each other that the A tract changes slightly andthe peripheries present the A forms. The holes are clear forboth DNAs, indicating the distinct changing from B to Aform. However, the distributions of these two ions are quitedifferent in that Na+ ions concentrate around the centralbackbones while some K+ ions permeate into the minorgroove. DNA remains B form with narrow and deep minorgroove and completely wide and shallow major groove asRb+ or Cs+ ions added (Figure 4(d) and 4(i), and Fig-ure 4(e) and 4(j)). The holes in the centre become small ormainly disappeared. Most of Rb+ and Cs+ prefer residingin the grooves rather than binding around backbones andbind mainly at the A tract, similar with the former studies[29,31].

To evaluate the DNA structure changes in detail, eightdistinct parameters, which are very distinguishing betweenA and B forms, are calculated both in λ= 0.6 and nor-mal water as the comparison, and the average values of

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2712 J. Wen et al.

Figure 5. Averaged DNA structure parameters during the last 20 ns simulations. They are the X displacement (Xdp), inclination angle(Inc) of a base pair from the helical axis, sugar pucker angle (Phi), end-to-end length (Len), width (MW and mW) and depth (MD andmD) of minor and major grooves. The plain bar charts indicate the values in the less polarised solvent. The green (light grey) and violet(dark grey) short lines present the values of typical A and B forms, respectively.

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Molecular Physics 2713

inner eight base pairs are presented in Figure 5. It suggeststhat each value of parameter keeps around B form in nor-mal SPC solvent, similar to many studies indicated before[41,45]. No alkali metal ions can change the structure ofDNA although the ions distribute differently around DNA.However, as the charge scale decreases to 0.6, the valuesappear completely different with these five alkali metalions that Li+ ions change the DNA conformation the mostwhile Cs+ ions the least. For Li06, all of the parametersare close to A values except MW and Phi. They are 8.23 Aand 54.35◦, respectively, locating in the area between Aand B values (named (A-B) mix). As to Na+ and K+ ions,most values are similar – mD, mW, MD, Inc and Len stableclose to A values, MW and Phi between A and B. How-ever, XdpK06 (3.92 A ) is close to XdpLi06 but larger thanXdpNa06 (3.45 A ). Taken as a whole, it is worth mentioningthat the values of DNA conformation for these three lighterions are changed to the A value. However, most parame-ters keep the B form similar to that in normal solvent forRb+ and Cs+ , when XdpRb06 and IncRb06 are changed to(A-B) mix values, around 2.23 A and 6.34◦, respectively.These phenomena show that the capability of alkali metalions changing the structure of preferred B-DNA decreasesas the mass number increases in less polarity solvent.

The above conformation preference of DNA is similarto the phenomenon that right-handed DNA duplexes as-sume B form at high water activity and A form at reducedlevels [77,78]. It seems that polarisation of solvent deter-mines whether the conformation transition happens or notand the ionic effects are more definitive. The free phos-phate oxygen atoms along the DNA backbone are hydratedin the solution, and the hydration can screen the repulsionbetween the negative oxygen atoms, which can be called‘economics’ of phosphate hydration. Solvent moleculesalso can form a network arching across the opening ofDNA grooves, just like a spin of water. The spin of hydra-tion down the minor groove of DDD. Both the screening ofrepulsion and spine of water in grooves may influence theconformation of DNA. Ions can change the conformation ofDNA by destroying the structure of water. In former studies[79,80], electrostatic model proposes that DNA conforma-tion and dynamics are affected by the positions and fluctua-tions of ions through their association with electronegativesites in DNA. There still are debates on these DNA heliceschanges that whether the ‘economics’ of phosphate hydra-tion or the minor groove ‘spine of hydration’ affects thisprocess. To check the underlying cause of the conforma-tion transition induced by the ions and solvent polarity, weevaluate the hydration and counterion competition aroundthe phosphate groups and in the grooves of DNA helix,respectively.

The RDFs of g(r)ions and g(r)H2O are shown inFigure 6(a) and 6(b). When the mass number increases fromLi+ to Cs+ , the first peak of g(r)ion decreases from over400 to below 100. The ability of alkali metal ions coupling

to the free oxygen atoms becomes weaker and weaker withthis order. Meanwhile, the first peak of g(r)H2O increasesslightly (from 1.26 to 1.68) as mass number increases. ForLi06, Li+ ions tightly bind to the phosphate oxygen atomsin preference to solvent molecules, the first peak of g(r)Li+

reaches over 435 at 2.12 A. The first peak of g(r)H2OLi06 isjust 1.26, half of that in normal solvent (figure is not shown).This strong interaction between Li+ and the free phosphateoxygen atoms restrains the electrostatic repulsion on thebackbones. Na+ ions couple to the electronegative oxygenatoms strongly though the maximum of g(r)Na+ is twice lessthan g(r)Li+ . The maximum of g(r)H2ONa06 is similar to that ofg(r)H2OLi06 . Na+ ions are yielded from the contacting sitesaround backbones but no more hydrations permeating, stillshielding the free phosphate oxygen atoms from hydrogenbond invading.

For K06, the maximum of g(r)K+ decreases to 118 andg(r)H2OK06 increases to 1.51, K+ ions also screen the repul-sion between negatively charged phosphate groups, keepingDNA as A form. However, Rb+ and Cs+ ions are unable toshield the free phosphate oxygen atoms completely for thedecreasing ion–backbone interaction notwithstanding boththe first peaks of g(r)Rb+ and g(r)Cs+ exceeding 80. Hydra-tion shields and dominates the electronegative sites aroundbackbones with both maxima of g(r)H2ORb06 and g(r)H2OCs06

reaching 1.60.The coordination numbers (abbreviated as CN) of ions

and the solvent molecules around negatively charged oxy-gen atoms of phosphate groups are presented in Figure 6(c)and 6(d). CN is the integration of the corresponding RDFand the lines in figures present the CN in the first hydra-tion shell or at the direct interaction sites. In Figure 6(c),it seems that one Li+ or Na+ is strongly coordinated tothe free phosphate oxygen atoms, forming strong ion−O(P)interaction and restraining the electrostatic repulsion on thebackbones. However, the average CNs of K+ , Rb+ andCs+ are all around 0.85.

Referring to Figure 4, it can be deduced that K+ , Rb+

and Cs+ ions locate around the centre part instead ofperipheries of the backbone, the binding sites of the pe-ripheries are left to hydration. Both CNs of the solventmolecules in Li06 and Na06 increase to 6.2 at 3.2 A, whichare less than that in the other cases because of the occupancyof Li+ and Na+ in the first shell. These phenomena ex-plain that is preferred ‘economics’ of phosphate hydration.The lighter ions (Li+ and Na+ ) screen the repulsion be-tween two negatively charged phosphate groups and DNAexperiences the B → A conformation translation. Mean-while the heavier ions (Rb+ and Cs+ ) can not shield thewhole backbone that the repulsion just extends the helix atthe peripheries without conformation transition. However,K+ ions also change the B-DNA to A-DNA and the back-bone is not totally screened, meaning that there are otherforces influencing the structure besides the ‘economics’ ofphosphate hydration.

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Figure 6. Radial distribution functions (RDFs) (a), (b) and corresponding coordination numbers (c), (d) of ions (a),(c) and watermolecules (b),(d) around negative oxygen atoms of the phosphate groups in less polarised solvent. The lines in (c) and (d) show thecoordinate numbers in the first shell around the backbone. The inset is the RDFs of these five ions with solvent molecules.

As to Hofmeister effect, it can be seen that both Li+ –O(P) and Li+ –H2O interactions are the strongest whilethose of Cs+ are the weakest in Figure 6(a) and inset,which means that the water structure is broken mostly byLi+ , while the ions interact with DNA closer than solvent.In less polarised solvent, water molecules repulse the ionsaway and ions bind around DNA, these ions disturb thestructure of water. The phenomenon here is similar to thatin high polarised solvents [76]. Comparing with the situa-tion in the normal water solvent, the order of Hofmeistereffects is Li+ > Na+ > K+ > Rb+ > Cs+ in less po-larised solvent. Both the DNA conformation transition andHofmeister series are influenced by the polarity of water.

RDFs and CNs of ions around atoms in the minor grooveare also calculated in Figures 7(a) and 8(a) to study the‘spine of hydration’ effects on conformation transition. Onone hand, none of Li+ and Na+ ions can permeate intothe minor groove though mW becomes wider and mD shal-lower. They just locate at the fringe of the minor grooveand interact indirectly with the base pairs. For the lighter

ions, the ‘economics’ of phosphate hydration is dominant.On the other hand, Rb+ and Cs+ ions directly couple toall of the atoms in the minor groove except N3 of guanine(GN3). The first peaks of g(r)Rb+ and g(r)Cs+ reach 18 and15 at A tract, respectively. Their CNs exceed 0.2 at O2 ofthymine (TO2). This suggests that at least one Rb+ or Cs+

ions locate in the first shell of ‘spine of hydration’ and isshared by the A tract. The ApT steps are dominated bythe effect of ‘spine of hydration’. K+ ions also stronglyinteract with the atoms in the minor groove that the max-imum of g(r)K+−TO2 is 22.5, close to that of g(r)Rb+−TO2

and g(r)Cs+−TO2. However, the CN of K+ at A tract is 0.15,half of the CN of Cs+ , which indicates a strong but un-steady K–base pair interaction. It seems that K+ ions bal-ance the phosphate hydration and the ‘spine of hydration’effects.

RDFs and CNs of ions around atoms in the majorgroove are also presented in Figures 7(b) and 8(b) to ex-amine whether the ions in the major groove influence theconformation equally with that in the minor groove. Li+

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Figure 7. Radial distribution functions (RDFs) between the cations (Li+ , Na+ , K+ , Rb+ and Cs+ ) and (a) O2 of the cytosine, (b) N3of the guanine, (c) N3 of the adenine, (d) O2 of the thymine, (e) N7 of the guanine, (f) O6 of the guanine, (g) N7 of the adenine and (h)O4 of the thymine in less polarised solvent. (a)–(d) give sites in the minor groove and (e)–(h) show sites in the major groove.

ions appear at N7 of guanine (GN7) and O4 of thymine(TO4) and g(r)s are 58.23 and 36.45, respectively. Na+

ions locate around O6 of guanine (GO6) and N7 of adenine(AN7), g(r)Na+−GO6 is close to 80. As to K+ and Rb+ , they

can be found in all four sites except TO4. The maxima ofg(r)K+−GO6 and g(r)K+−GO6 reach 110 and 60, respectively.Cs+ ions dominate the whole major groove that all g(r)Cs+sexceed 10. As for CN, five ions can enter into the major

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Figure 8. Coordination numbers (CNs) between the cations(Li+ , Na+ , K+ , Rb+ and Cs+ ) and the atoms in the groovesfor less polarised solvent. (a) is that of minor groove and (b) themajor groove.

groove and the CNs at G tract are larger than that at A tract,indicating that more alkali metal ions prefer to locate atthe peripheries of the major groove. The ionic distributionsinfluence the DNA structure little.

The CNs of alkali metal ions around the negativelycharged phosphate groups and the atoms at the A tract ofthe minor groove are compared in less polarised and normalsolvent in Table 2, respectively. The CNs are similar for allfive ions in normal solvent with the concentration around0.82 at backbone and 0.18 at the A tract, and the DNA con-formations are changed little. However, the CNs of Li+ andNa+ are totally different in less polarised solvent that theCNs with phosphate oxygen ions (CNO(P)s) exceed 1 whilethe CNs with base pairs (CNBPs) decrease to 0. CNO(P) ofK+ reaches 0.903 and CNBP is 0.172. As to Rb+ and Cs+ ,CNO(P)s are stable and CNBPs increase to 0.20. Relating tothe conformation transition, it seems that CNBPs influencethe structure little while CNO(P)s determine the final DNAconformation. Moreover, there is a CNO(P) threshold value

Table 2. Coordination numbers (CN) of Li+ ,Na+ , K+ , Rb+

and Cs+ ions with the negatively charged phosphate groups(CNO(P)) and the A tract in the minor groove (CNBP) in less po-larised (LP) (λ = 0.6) and normal solvent (NR).

Li+ Na+ K+ Rb+ Cs+

CNO(P)LP 1.052 1.043 0.903 0.813 0.805CNO(P)NR 0.832 0.829 0.828 0.815 0.812CNBPLP 0 0 0 0 0CNBPNR 0.173 0.175 0.178 0.182 0.181

between 0.8 and 0.9 that no structure changing is observedwhen CNO(P) is lower than the value and the B → A formtransition happens with the values higher than it.

For Li06 and Na06, the repulsion between negativelycharged phosphate groups is screened, driving the ‘eco-nomics’ of phosphate hydration being the most commonlyconcerned conformation transition factor. Though stronglyinteracting with phosphate of DNA, heavier ions (Rb+ andCs+ ) can not affect the first shell around phosphates muchfor the bigger radius in less polarised solvent. Furthermore,heavier ions bind in the first shell of minor groove thanlighter ions because of the longer residence time (the res-idence times of Rb+ and Cs+ reach 12.77 and 13.96 ps,respectively, while that of Li+ and Na+ are just 1.32 and1.43 ps, respectively). The heavier ions break ‘spine ofhydration’ much easier than lighter ones. However, DNAhelices changing is not relevant to the ‘spine of hydration’in Rb06 and Cs06.

3.4. The behaviours of K+

In the process of DNA conformation transition, K+ ionsboth contact with the phosphate group and the atoms in theminor groove, and move around different binding sites atthe backbone and A tract. DNA conformation transition willhappen when the K+ ions strongly interact with both basepairs and backbones instead of just screening the repulsionbetween different negatively charged phosphate groups.

To understand the relationship between K+ –DNA in-teraction and the structure changing, the root mean squarecoordinate deviation (RMSD) of the DNA trajectorieswith respect to canonical B and canonical A is shown inFigure 9, in contrast with the changing of CNO(P) and CNBP

with time. There are high RMSDs appearing during DNA

Figure 9. Root mean square coordinate deviation (RMSD) of theDNA trajectories in K+ solution with respect to the canonical B(orange or light grey) and A (blue or dark gray) forms. The insetshows the changing of the coordination numbers with phosphateoxygen atoms – CNO(P) (solid line) and the coordination numberswith base pairs – CNBP (dashed line) with the simulation time inless polarised solvent.

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conformation transition here, similar to the former studiesby Cheatham III et al. [81]. For less polarised solvent, theDNA changes from B form to a stable A form during thefirst 2 ns, after that the RMSD with respect to A form isless than 3 A with fluctuations less than 0.2 A. In the mean-while, the CNO(P)s are around 0.95 while the CNBPs arejust 0.09 in the first 6 ns, very close to the value of Li+

and Na+ , which suggests that one K+ is strongly coordi-nated to the free phosphate oxygen atoms in the processof DNA conformation transition. The structure changingmechanism in K06 is similar to that in Li06 and Na06 atfirst 6 ns. After the A form stabilising, the CNO(P) decreasesto 0.84 and CNBP increases to 0.21. K+ ions are dispersedfrom backbone and attracted by the base pairs. The RMSDdoes not fluctuate as the CNO(P) decreases, it seems that lessK+ ions can steady the A form. After 15 ns, the CNO(P)

and CNBP stably maintain around 0.90 and 0.17, respec-tively. All these phenomena demonstrate that K+ is moreflexible than the other alkali metal ions that they balancethe forces between negatively charged phosphate group andbase pairs. Furthermore, the forces screening repulsion dur-ing the process of A–B conformation transition are largerthan that stabilising the A form.

The ‘economics’ of phosphate hydration is the main fac-tor influencing DNA conformation transition for all alkalimetal ions except K+ ions. It can be seen that the ‘eco-nomics’ of phosphate hydration and minor groove ‘spine ofhydration’ influence the DNA conformation together in thecase of K06. First, K+ ions prefer to locate at phosphateand DNA conformation transition happens. Then they dockin the minor groove and the A form begins to stabilise.At last, some K+ ions bind back to the phosphate andA form keeps stable. It suggests that the screening of therepulsion between phosphate groups is the essential con-dition to start transition and the breaking of the ‘spine ofhydration’ is the sufficient condition to finish transition inK06. Referring to our previous study [39], the behavioursof K+ are quite special in some extreme conditions (suchas the higher temperature and less polarised solvent),which help us understand the significance of K+ in livingorganisms.

4. Conclusions

A specific structure is crucial for DNA to perform its correctbiological activity or any other novel function. Five kindsof alkali metal ions (Li+ , Na+ , K+ , Rb+ and Cs+ ) arechosen to study the counterions effect and their Hofmeistereffects on a typical B form duplex d(CGCGAATTCGCG)in the less polarised solvent compared to normal solvent. Inless polarised solvent with the increasing of mass numberfrom Li+ to Cs+ , the DNA becomes more and more rigid.For Li+ , Na+ and K+ ions, the structure of DNA changesfrom B-DNA to A-DNA. As to Rb+ and Cs+ ions, DNAkeeps the B form after 40 ns simulations. The long-range

intra-molecule electrostatic interaction in the nucleotide se-quence is crucial to keep the stable conformation and canbe modulated by the competition between hydration andthe ion coupling to the free phosphate oxygen atoms. Li+

and Na+ can efficiently restrain the electrostatic repulsionbetween phosphate groups while the free oxygen atomsare mainly coupled by hydrations in Rb06 and Cs06. Thebehaviours of K+ ions are different with the others thatthey both coordinate strongly with backbone and base pairsduring DNA conformation transition.

The CNO(P) and CNBP of K+ indicate a potential barrierof the A–B conformation transition indirectly. The bindingenergies of Rb+ or Cs+ ions with backbone can not crossover this barrier and the DNA performs B form. The inter-mediate (A-B) mix states exist under micro-environment,for example, when DNA combines with protein, the mildestconditions are not presented in our simulations here. Itseems that the potential barrier does not have any mini-mum during DNA conformation transition in our solutionenvironments. The less polarised solvent changes the po-tential barrier of A and B form structure changing.

The Hofmeister effect from ‘chaotrope’ to ‘kos-motropes’ is ordered as Li+ > Na+ � K+ � Cs+ � Rb+

in normal solvent and Li+ > Na+ > K+ > Rb+ > Cs+

in less polarised solvent. The clear Hofmeister effect ob-tained in less polarised solvent reflects the importance ofinteractions between ions and waters. The studies suggestedthat Hofmeister ions affecting one property will also sig-nificantly influence other properties [76]. The Hofmeisterseries and DNA conformation transition are affected bypolarity of solvent. In addition, the series in less polarisedwater may also influence DNA conformation transition, andvice versa.

Despite the simplicity of the charge scaled water model,we construct the highly distorted solvent model but keep thesame size of solvent molecule with unchanged geometry.The polarity of water model here is similar with organicsolvent model and the results in this paper are consistentwith experimental phenomena, which give a clear molecularlevel description of the conformational preferences of DNAhelices in water instead of organic liquids.

FundingThis work was supported by the National Natural ScienceFoundation of China [grant number 11025524], [grant number11161130520]; National Basic Research Programme of China[grant number 2010CB832903]; the European Commission’s7th Framework Programme (FP7-PEOPLE-2010-IRSES) [grantagreement project number 269131].

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