Polymorphism and Flexibility of DNA in Alcohols

Nan Zhang(张楠)$^{1,2}$, Ming-Ru Li(李明儒)$^{1,2}$, Hui-Ting Xu(徐慧婷)$^{1,2}$, and Feng-Shou Zhang(张丰收)$^{1,2,3\hyperlink{s}{*}}$

doi:10.1088/0256-307X/37/8/088701

⇦Chinese Physics Letters, 2020, Vol. 37, No. 8, Article code 088701⇨ Polymorphism and Flexibility of DNA in Alcohols Nan Zhang (张楠)1,2, Ming-Ru Li (李明儒)1,2, Hui-Ting Xu (徐慧婷)1,2, and Feng-Shou Zhang (张丰收)1,2,3* Affiliations 1The Key Laboratory of Beam Technology and Material Modification of Ministry of Education, College of Nuclear Science and Technology, Beijing Normal University, Beijing 100875, China 2China Beijing Radiation Center, Beijing 100875, China 3Center of Theoretical Nuclear Physics, National Laboratory of Heavy Ion Accelerator of Lanzhou, Lanzhou 730000, China Received 19 April 2020; accepted 27 May 2020; published online 28 July 2020 Supported by the National Natural Science Foundation of China (Grants Nos. 11635003, 11025524 and 11161130520), the National Basic Research Program of China (Grant No. 2010CB832903), and the European Commission's 7th Framework Programme (Fp7-PEOPLE-2010-IRSES) (Grant No. 269131).
^*Corresponding author. Email: fszhang@bnu.edu.cn Citation Text: Zhang N, Li M R, Xu H T and Zhang F S 2020 Chin. Phys. Lett. 37 088701 Abstract Molecular dynamics simulations are performed to investigate the polymorphism and flexibility of DNA in water, ethylene glycol (EG) and ethanol (EA) solutions. DNA in EG resembles the structure of DNA in water exhibiting B-DNA. In contrast, the DNA is an A-DNA state in the EA. We demonstrate that one important cause of these A$\leftrightarrow$B state changes is the competition between hydration and direct cation coupling to the phosphate groups on DNA backbones. To DNA structural polymorphism, it is caused by competition between hydration and cation coupling to the base pairs on grooves. Unlike flexible DNA in water and EA, DNA is immobilized around the canonical structure in EG solution, eliminating the potential biological effects of less common non-canonical DNA sub-states. DOI:10.1088/0256-307X/37/8/088701 PACS:87.10.Tf, 87.14.gk, 87.15.B-, 31.15.xv © 2020 Chinese Physics Society Article Text The polymorphism and flexibility of DNA play a significant role in protein-DNA specific binding, the interaction between drug molecules and DNA, and the design of emerging biomolecular devices.[1–4] Similar effects can be expected to play a role in the majority of physiological processes involving DNA: packaging, repair, replication, gene expression, and so on.[5–7] The diversity of DNA structure is not only affected by an internal factors DNA base sequence, but also by the complex physiological environment (aqueous solvent, proteins, ions, and even pharmaceutical drug) in cells.[8–10] Many molecular dynamics (MD) simulations report the polymorphism and flexibility of DNA molecules. Most of the MD simulations released 10 years ago were performed in duration of 1–10 ns, although several simulations covered dozens of nanoseconds. The two force fields of CHARMM and AMBER used to be the mainstream in the field of DNA simulation until multi-nanosecond simulation revealed the server's artifacts. Over the past few decades, two field families AMBER and CHARMM have dominated DNA simulation until multi-nanosecond simulation reveals server artifacts. Parmbsc0 is proposed to refine the AMBER parm98 force-field backbone parameters to improve consistency with the experiment.[11] The Orozco group presented the first microsecond MD simulation of DNA in water on a biologically timescale, which supports major reversible conformation conversion at a timescale from picoseconds to microseconds.[12,13] In turn, in the microsecond system, Parmbsc0 begins to show deviations from experimental data. The Parmbsc1 force field is used to address the underestimation of twist, deviations in sugar puckering, biases in $\varepsilon$ and $\zeta$ torsion, excessive terminal fraying, and other problems representing in Parmbsc0 force field.[14] The Ascona B-DNA consortium (ABC) and the Sarai group simulated and analyzed B-DNA oligomers containing all 136 tetrameric base sequences.[15–17] The base sequence effects is not only strongly dependent on the specific base pair step, but also dependent on the specific base pairs on the flank of each step. Lavery team provides a new method for analyzing the distribution of ions or molecules around helical nucleic acids in MD simulations.[18,19] This analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. Our group investigated the precise mechanism of radiation-induced DNA damage, occurring in a fluctuating environment under specific local physical conditions of water and ions.[20–24] When the polarity of the solvent molecule decreases, from over polarized to less polarized, DNA experiences the conformational transitions of constrained $\text{B form} \rightarrow \text{A–B mixed} \rightarrow$ A form. All of the above studies are the polymorphism and flexibility of DNA segment in the water environment. An interesting basic question is which fundamental property of its molecule distinguishes water as the most important solvent in nature.[25] Are there any other liquids that support biological activities? It is generally accepted that polarity and hydrogen bonds (HBs) are significant properties of water compared to other liquids.[26] DNA has been observed to retain its natural double-stranded structure in ethylene glycol (EG) salt solution.[27,28] The biological activity of DNA in EG was investigated by following the transforming activity of Bacillus subtilis DNA with competent bacteria.[29] DNA can keep its biological activity after long time periods in EG salt solutions. However, the polymorphism and flexibility of DNA in EG has been little investigated during the last half-century. Compared with aqueous solution, EG solution has the following advantages: (I) It seems possible that the radiation damage of DNA in EG may be weaker than the radiation damage in water, since hydroxyl radicals would not be generated in similar amounts in EG solutions. (II) The EG may present a cheaper and more efficient option for storing DNA in bio-banks than in frozen aqueous buffer solution. EG may provide better protection for DNA against cosmic radiation, hence facilitating its safe interplanetary transport. In this letter, we focus on the polymorphism and flexibility of DNA in EG solutions, and compare the results with those in aqueous solution and EA solution. The properties of the liquid alcohols (water, EG and EA) are discussed in our previous article.[30] The polymorphism and flexibility of DNA in alcohols were investigated based on the GROMACS code package for molecular dynamics simulations.[31] The periodic cube box contains one DNA 12-mer, 150 mM NaCl and 5025 solvent molecules, the solvent molecules were water molecules, EG molecules or EA molecules, respectively. The mechanical evolution of DNA oligomers in alcohols was described by the Parmbsc1 force field.[14] The initial DNA structure was selected as the Drew–Dickerson dodecamer (d(CGCGAATTCGCG)) with PDB ID: 171d. Water was modeled using the tip3p parameters, a long-timescale molecular dynamics simulations have found that the conformation characteristics of DNA are insensitive to water models.[13] Electrostatic interactions were dealt with the particle mesh Ewald summation method using a cut-off of 1.2 nm for the interaction range, with the real-space cut-off set at 1.0 nm and the Lennard–Jones interactions cut-off set at 1.0 nm.[32,33] LINCS was used to restrain all chemical bonds involving hydrogen atoms.[34] The center of mass motion was removed every 5000 steps to avoid kinetic energy building up in translational motion and keeping the solute centered in the simulation cell.

Fig. 1. Averaged DNA structure parameters during the last 100 ns simulations. They are the $X$-displacement and inclination angle of a base pair from the helical axis, width (MW and mW), and depth (MD and mD) of minor and major grooves. The horizontal lines indicate the reference values of typical A (green) and B (pink) forms.

Fig. 2. Averaged DNA structure parameters during the last 100 ns simulations. They are the slide, roll and twist angle of inter base pair parameters and intra-base pairs parameter propeller. The horizontal lines indicate the reference values of typical A (green) and B (pink) forms.

With the aim of assessing the DNA structure changes in aqueous, EG and EA, we extracted 10 distinct parameters, which distinguish between A and B states, are calculated and presented in Figs. 1 and 2. In the solvent of water and EG, the grooves and intra-base pairs are all near B-DNA value, axis-base pairs and inter-base pairs are located in the middle area between A and B DNA, but closer to B, belonging to the B-DNA state. As to EA, the slide maintains the value of B-DNA, while the other parameters are close to A or situated in the intermediate region between A and B states. This transitional state of the DNA segment in EA solutions is assigned to A-DNA state. If we extend the above analysis, as B-DNA, we will see the disparity of DNA structures in the case of water and EG. For the axis-base pairs parameter $X$-displacement, in both solutions, a moderate displacement of base pairs towards the negative direction of $X$-axis (major groove direction) is observed. We can also note that in the EG solution, the base pair is more favorable for displacement to the major groove. As the water molecules are replaced by EG molecules, both the major groove width and minor groove width are broadened, and the minor groove depth becomes shallow. Groove width is a key requirement to achieve good complementary in the binding of DNA to small ligands or proteins. In EG, the inter-base pair parameters exhibit a low slide and low twist, which is a few degrees smaller than that in the aqueous solution. In water and EG, the propeller is distributed around $-11^\circ$ and $0^\circ$, respectively. There is no surprise that propeller deformation events are more commonly found in A$\cdot$T pairs. The reason for propeller deformation may reflect the stability of HBs between base pairs, while the HB number between A$\cdot$T base pairs is small. It has been suggested that the molecular origin of these DNA structural transitions is related to solvent accessibility, base stacking interaction, phosphate hydration, minor groove spine of hydration, and the negatively charged phosphate groups screened.[35–38] To check the underlying cause of the structural transitions induced by the solvent, we evaluate the counter-ion distribution around the DNA segment. The ion distribution surrounding the nucleic acid was analyzed using the CANION program.[19]

Fig. 3. Two-dimensional ${\rm Na}^{+}$ molarity (aM) distribution around DNA in aqueous solution, as a function of the (a) RA, (b) DR and (c) DA. The molarity increases going from blue to red, in discrete, non-uniform steps chosen to highlight the structure of the distribution. The white circle in RA and vertical bars in DR indicates the phosphorous radius ($R = 10.25$ Å), while the RA and DA plots show the minor groove limits $33^\circ$–$147^\circ$, defined by the average C1' positions, as white radial vectors and as a white line, respectively.

We can now look in more detail by 2D representations. Figure 3 shows the RA, DR, and DA maps of ${\rm Na}^{+}$ ions around the oligomer. In the graph of RA, we can see that ${\rm Na}^{+}$ is closer to the helix axis on the side of the major groove. It is no doubt that the major groove is wider and easier to accept ions approach to the helical axis. It should also be noted that there is only one ion strongest binding site at the center of the minor groove, while we see two molarity peaks within the major groove. A more diffused molarity distribution is located in the external region of the minor grooves, and surrounding the negatively charged phosphate groups to screen for electrostatic repulsion. The DR image shows the strongest ions-nucleotide interactions happen in the major groove at the center ${\rm d}({\rm AATT})_{2}$ segment. A strong, very localized region of high Na$^+$ molarity is found in the minor groove, with Na$^+$ being mainly coordinated to C$\cdot$G. More diffuse binding regions are located in the external region of the minor grooves ${\rm d}({\rm AATT})_{2}$ segment. In summary, we found a strong ion binding zone in the major groove at ${\rm d}({\rm AATT})_{2}$ segment and in the minor groove of C$\cdot$G base pairs. The external region of the minor grooves ${\rm d}({\rm AATT})_{2}$ segment and the phosphoric acid backbine are shown as ion secondary binding regions. In order to complete the ${\rm Na}^{+}$ ion analysis in the EG solution, it is useful to look at the 2D ion distributions, as plots in Fig. 4. Looking at the RA plot we can also see that the highest molarity in the minor groove lies in a continuous zone spanning the center of the groove, while the major groove density shows four distinct peaks. Looking at the ${\rm Na}^{+}$ in the external region of the minor grooves ($R\approx12$ Å) we again see that the high molarity corresponds to the grooves and not to the phosphate groups. The DR image shows that the strongest ions-nucleotide interactions happen in the internal region of the groove at ${\rm d}({\rm CGCGAATTCGCG})_{2}$ sites and the diffuse bonding region in the external region of the minor groove of the central ${\rm d}({\rm ATT})_{2}$ segment. The ${\rm d}({\rm CGCGAATTCGCG})_{2}$ sites in the EG solution is a strong ion binding zone, and the external region of the minor grooves ${\rm d}({\rm ATT})_{2}$ segment is shown as ion secondary binding regions.

Fig. 4. Two-dimensional ${\rm Na}^{+}$ molarity (aM) distribution around DNA in ethylene glycol solution, as a function of RA, DR and DA. The molarity increases going from blue to red, in discrete, non-uniform steps chosen to highlight the structure of the distribution. The white circle in RA and vertical bars in DR indicates the phosphorous radius ($R = 10.25$ Å), while the RA and DA plots show the minor groove limits $33^\circ$–$147^\circ$, defined by the average C1' positions, as white radial vectors and as a white line, respectively.

Fig. 5. Two-dimensional ${\rm Na}^{+}$ molarity (aM) distribution around DNA in ethanol solution, as a function of RA, DR and DA plane. The molarity increases going from blue to red, in discrete, non-uniform steps chosen to highlight the structure of the distribution. The white circle in RA and vertical bars in DR indicates the phosphorous radius ($R = 10.25$ Å), while the RA and DA plots show the minor groove limits $33^\circ$–$147^\circ$, defined by the average C1' positions, as white radial vectors and as a white line, respectively.

The ${\rm Na}^{+}$ ions are mainly bound to the phosphate oxygen atoms in EA solvents, as shown in Fig. 5. One important cause of the A$\leftrightarrow$B state changes in alcohols is the competition between hydration and direct cation coupling to the free oxygen atoms in the phosphate groups on DNA backbones. In aqueous or EG, the free phosphate oxygen atoms are primarily shielded by solvent molecules through hydrogen bonding with positively charged protons in the first hydration shell, ${\rm Na}^{+}$ ions are more dispersed, exhibiting B-DNA. In EA solution, ${\rm Na}^{+}$ is strongly coordinated to a free phosphate oxygen atom, forming chemical bonds ${\rm Na}^{+}$–${\rm O}^{-}$(P) and restraining the electrostatic repulsion on the backbones. Consequently, the DNA prefers the shorter and more compacted A form. DNA structural parameter polymorphism, which is caused by competition between hydration and cation coupling to negative atoms in the base pairs on DNA grooves. Unlike aqueous solutions, the ion distribution in the EG solution shows two interesting features: first, in the middle ${\rm d}({\rm AATT})_{2}$ fragment, sodium ions are only distributed outside the minor groove and do not appear in the internal region of the major groove. There is competition between the solvent and ${\rm Na}^{+}$ ions in the major groove of the ${\rm d}({\rm AATT})_{2}$ fragment.[12] ${\rm Na}^{+}$ will coordinate with O2 of thymine in the major groove of ${\rm d}({\rm AATT})_{2}$, breaking hydrogen bonds of A$\cdot$T pairs and amplifying the propeller.[12] Therefore, propeller deformation events are more commonly found in aqueous solution. Secondly, in C$\cdot$G pairs, the molar density distribution of ${\rm Na}^{+}$ is several times that of the aqueous solution. Orozco's team provided a detailed picture of cation arrangements associated with structural parameter polymorphism.[16] The cations enters the minor groove of the C$\cdot$G pairs, promoting low twist/slide conformational transition and an increase in the width of the minor groove, corresponding to the general structure of DNA segment in EG. A previously unexplored intramolecular C8H8$\cdots$O3' formed to stabilize the low twist state. The rule of cation interact with A$\cdot$T differs from the case of C$\cdot$G pairs. DNA is a very flexible polymer, and this property is crucial for understanding that a wide range of conformation DNA can be adopted under physiological conditions.[39] Mining MD trajectories to extract information about DNA flexibility is not easy and can be approached in different ways. One of them is based on techniques such as PCA, which captures the deformation profile of the molecule (eigenvectors) and the relative importance of the eigenvectors (associated eigenvalues). A similar analysis can be performed on the DNA's natural helical space described by three translations (shift, slide, rise) and three rotations (tilt, roll, twist) relating the two base pairs of a base pair step. Phosphorus distributions can be used to determine the flexibility of the duplex in alcohols, and the phosphorus distribution are given in Fig. 6. The phosphorus distribution indicates that the dodecamer is not behaving like an ideal rod, but has solvent dependent flexibility. The flexible phosphorus distribution obtained in water and EA simulations is quite similar, but phosphorus is firmly to the regions around canonical values in EG solution, removing the less prevalent potential biological impacts of non-canonical DNA sub-state.

Fig. 6. Phosphorus molarity (aM) distributions plotted in various solvents: water (left), ethylene glycol (center) and ethanol (right). DA plots show the minor groove limits $33^\circ$–$147^\circ$, defined by the average C1' positions, as a white line.

Whether as a carrier of genetic information or a basic unit of emerging molecular devices, the correct structure is the basis for the realization of DNA functions. We have presented the polymorphism and flexibility of DNA in alcohols by using molecular dynamics simulations. The double-stranded DNA in salt-containing EG solutions resembles the structure of DNA in aqueous solutions, with its characteristic of expanding groove width, low-twist, low-slide and stable propeller structure, exhibiting B-DNA. In contrast, the DNA structure is an A-DNA state in the EA solution. B-DNA and A-DNA are common functional structures of double-stranded DNA. During the interaction of DNA with some proteins or RNA, some parts of DNA molecules will have a relatively stable (A-B) mixed state. Unlike flexible DNA in water and EA solutions, DNA is fixed around the canonical structure in the EG solution, eliminating the potential biological effects of less common non-canonical DNA sub-states. To check the underlying cause of the structural transitions induced by the solvent, we evaluate the counter-ion distribution around the DNA segment. In aqueous, we found a strong ion binding zone in the major groove at ${\rm d}({\rm AATT})_{2}$ segment and in the minor groove of C$\cdot$G base pairs. The external region of the minor grooves ${\rm d}({\rm AATT})_{2}$ segment and the phosphoric acid backbone are shown as ion secondary binding regions. The ${\rm d}({\rm CGCGAATTCGCG})_{2}$ sites in the EG solution is a strong ion binding zone, and the external region of the minor grooves ${\rm d}({\rm ATT})_{2}$ segment is shown as ion secondary binding regions. The ${\rm Na}^{+}$ ions bind to the phosphate oxygen atoms in solvents of EA. We demonstrate that one important cause of these A$\leftrightarrow$B state changes is the competition between hydration and direct cation coupling to the free oxygen atoms in the phosphate groups on DNA backbones. In aqueous or EG, the free phosphate oxygen atoms are primarily shielded by solvent molecules through hydrogen bonding with positively charged protons in the first hydration shell, ${\rm Na}^{+}$ ions are more dispersed, exhibiting B-DNA. In EA solution, ${\rm Na}^{+}$ is strongly coordinated to a free phosphate oxygen atom, forming chemical bonds ${\rm Na}^{+}$–${\rm O}^{-}$(P) and restraining the electrostatic repulsion on the backbones. Thus, DNA presents the shorter and more compacted A form. To DNA structural parameter polymorphism, which is caused by competition between hydration and direct cation coupling to negative atoms in the base pairs on DNA grooves. Two detailed pictures of cation arrangements associated with DNA structural parameter polymorphism are provided. When ${\rm Na}^{+}$ enters the ${\rm d}({\rm AATT})_{2}$ segment of major groove, it coordinates with O2 in thymine and destroys hydrogen bonds of A$\cdot$T base pairs, amplifying the deformation of the propeller. When the cation enters the C$\cdot$G pairs of the minor groove, intramolecular bond C8H8$\cdots$O3' is formed to promote low twist/slide conformational transition and an increase in the minor groove width, corresponding to the polymorphism of the DNA segment in EG. The rule of cation interacting with A$\cdot$T is different from the case of C$\cdot$G pairs steps. References Potential functions and conformations in cycloalkanesHelix bending as a factor in protein/DNA recognitionSignatures of Protein-DNA Recognition in Free DNA Binding SitesStructural comparison of anticancer drug-DNA complexes: adriamycin and daunomycinAnalyzing Protein-DNA Recognition MechanismsThe role of DNA shape in protein–DNA recognitionFolding DNA to create nanoscale shapes and patternsThe solvation of NaCl in model water with different hydrogen bond strengthIon effects of Sr2+, Cs+ and I− on DNA in aqueous solutionsSimulation of DNA in water/ethanol mixtureRefinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ ConformersDynamics of B-DNA on the Microsecond Time ScaleLong-timescale dynamics of the Drew–Dickerson dodecamerParmbsc1: a refined force field for DNA simulationsA systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNAUnraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNAμABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNAAnalyzing ion distributions around DNAAnalyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamicsSolvent-Induced DNA Conformational TransitionSolvent effects on the conformation of DNA dodecamer segment: A simulation studyCompetition between Na

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