Changes in Microenvironment Modulate the B- to A-DNA Transition

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Computational Biochemistry

Changes in Microenvironment Modulate the B- to A-DNA Transition Hong Zhang, Haohao Fu, Xueguang Shao, Francois Dehez, Christophe Chipot, and Wensheng Cai J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.8b00885 • Publication Date (Web): 15 Feb 2019 Downloaded from http://pubs.acs.org on February 19, 2019

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Journal of Chemical Information and Modeling

Changes in Microenvironment Modulate the B- to A-DNA Transition Hong Zhang, † Haohao Fu, † Xueguang Shao, †,‡,# François Dehez, Christophe Chipot, †Research

⊥, $,

⊥

and Wensheng Cai*,†,#

Center for Analytical Sciences, College of Chemistry, Nankai University,

Tianjin Key Laboratory of Biosensing and Molecular Recognition, Tianjin 300071, China. ‡State

Key Laboratory of Medicinal Chemical Biology, Tianjin 300071, China

#Collaborative

Innovation Center of Chemical Science and Engineering, Tianjin,

300071, China

⊥

Laboratoire International Associé CNRS and University of Illinois at

Urbana−Champaign, SRSMC,

UMR

7019

Université

de

Lorraine

CNRS,

Vandœuvre−lès−Nancy F-54506, France $Department

of Physics, University of Illinois at Urbana−Champaign, Urbana, Illinois

61801, United States

1

ACS Paragon Plus Environment

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ABSTRACT: B- to A-DNA transition is known to be sensitive to the macroscopic properties

of

the

solution,

such

as

salt

and

ethanol

concentrations.

Microenvironmental effects on DNA conformational transition have been broadly studied. Providing an intuitive picture of how DNA responds to environmental changes is, however, still needed. Analyzing the chemical equilibrium of B-to-A DNA transition at critical concentrations, employing explicit-solvent simulations, is envisioned to help understand such microenvironmental effects. In the present study, free-energy calculations characterizing the B- to A-DNA transition and the distribution of cations have been carried out in solvents with different ethanol concentrations. With the addition of ethanol, the most stable structure of DNA changes from the B- to the A-form, in agreement with previous experimental observation. In 60% ethanol, a chemical equilibrium is found, showing reversible transition between B- and A-DNA. Analysis of the microenvironment around DNA suggests that with the increase of ethanol concentration, the cations exhibit a significant tendency to move toward the backbone, and mobility of water molecules around the major groove and backbone decreases gradually, leading eventually to a B-to-A transition. The present results provide a free-energy view of DNA microenvironment and of the role of cations motion in the conformational transition.

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INTRODUCTION DNA exists in many different forms, namely single-stranded, double-stranded and quadruplex DNA, which all possess different functions and properties.1,2 Double-stranded DNA, the main form in biological systems, can adopt different forms, namely the so-called A-, B- and Z-DNA. Transition between these conformations plays a central role in genetic regulation. For instance, B- to A-DNA transition is generally viewed as a key process during transcription.3 Binding with protein can also induce B-to-A transition in vivo.4-6 In aqueous solution, B form is the favored conformation, whereas the A form is found in low-humidity environment.7-9 Over the past twenty years, the subtle environmental

dependence

of

B-to-A

DNA

transition

has

been

largely

investigated.10-13 The water molecules14-18 and the mobile cations19-22 around DNA play a significant role on this conformational transition. Gu et al.23 have suggested that one important factor for B-to-A transition is the competition between hydration and electrostatic interaction of DNA with the surrounding cations. The dielectric constant and polarity of the solvent can also affect B-to-A transition.23, 24 Although the average solvation, electrostatic, and the mean solute internal energies have been determined,25-29 investigation of how the free energy varies concomitantly with DNA conformation and modifications of the environment remains limited.29 Changing the concentration of the water-ethanol mixture is a common approach 3



for regulating B- to A-DNA transition in vitro. A number of theoretical studies have focused on the equilibrium DNA structure in pure water or at high concentrations (around 80%) of ethanol.30-32 However, investigating the reversible B-to-A DNA transition in a critical environment, e.g., 60% ethanol, is of paramount importance. Due to the inherent complexity of the mixed solvent and the difficulty in defining a transition coordinate that accounts for all relevant degrees of freedom, the free-energy landscape that characterizes B- to A-transition coupled with the changes of DNA microenvironment has not been hitherto examined. To reveal the molecular mechanism that underlies the conformational transition, free-energy landscapes constitute a powerful tool.33 Banavali and Roux34 have explored that the difference in the root-mean-square deviations (ΔRMSD) relative to the canonical A- and B-DNA conformations, respectively, represents an effective transition coordinate to describe B- to A-DNA transition. Nonetheless, previous studies10-24 suggest that the DNA surroundings constitute crucial factors influencing the conformational transition. Thus, in the present study, two-dimensional free-energy calculations have been used to determine quantitatively the effect of the changes in the DNA microenvironment on the conformational free-energy characterizing B-to-A transition. From the investigation of the distributions and dynamic properties of the water molecules and cations around DNA, we suggest that the changes in microenvironment around DNA is essential for regulating B-to-A DNA transition.

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COMPUTATIONAL METHODS Molecular Models. The PDB code of the reference coordinates of the double-stranded A-DNA with sequence CCGGGCCCGG is 1ZF1.35 The NAB utility of Ambertools1636 was utilized to create the double-stranded B-DNA with the same sequence. As shown in Figure S1, the rise of A-DNA duplex per residue features a smaller value than B-DNA, and is, therefore, shorter. Moreover, the A-DNA base pairs are tilted by 20°, whereas those of B-form are perpendicular to the DNA axis.37-39 All the DNA structures simulated were described using CHARMM3640,

41

and AMBER bsc1 force fields.42 To investigate the solvent effect on the conformational transition of DNA, three simulations of an ethanol/water mixture with DNA were performed, wherein the weight percent of ethanol was 0%, 60%, and 80% (with 120Mm NaCl). The final boxes of 0%, 60%, and 80% ethanol solutions with the size of 62 × 62 × 62 Å3, contained 6289, 2261, 1096 water molecules, and 0, 1266, 1640 ethanol molecules, respectively, both with 33 Na+ and 15 Cl- ions. Molecular Dynamics Protocols. All the simulations were carried out utilizing the program NAMD 2.13.43 Langevin piston method and the Langevin dynamics were employed to maintain the temperature and pressure at 1 atm and 300K, respectively.44 Integration was performed with a r-RESPA multiple time-stepping algorithm45 with a time step of 4 and 2 fs for long- and short-range interactions, respectively. The SHAKE/RATTLE and SETTLE algorithms were utilized to constrain covalent chemical bonds involving hydrogen atoms to their experimental lengths.46-48 5



Long-range electrostatic forces were evaluated by the particle-mesh Ewald (PME) algorithm.49 To truncate short-range electrostatic and van der Waals interactions, a smoothed 12 Å spherical cutoff was used.49 Periodic boundary conditions (PBCs) were employed in the three directions of Cartesian space. The VMD 1.9.2.50 was applied to analyze and display the MD trajectories. Free-Energy Calculations. The initial structures of DNA were B-, B-, and A-form in the 0%, 60%, and 80% ethanol environment, respectively. The free-energy calculations describing the B- to A-DNA transition reported herein were carried out utilizing meta-eABF51 in one large window spanning the whole reaction pathway. The force instantaneous values were accrued in bins 0.1 Å × 0.1 wide. To determine each two-dimensional landscape, 1-µs sampling time was required. The least free-energy pathway connecting B- and A-DNA in the free-energy landscapes was determined by the LFEP algorithm.52

RESULTS AND DISCUSSION Transition Coordinate and Force Fields As depicted in Figure 1A, our preliminary 50-ns simulation, applying the CHARMM force field, shows that cations aggregate around the DNA major groove in the 80% ethanol solution. To reveal the role of the cations around DNA in the

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conformational transition of the latter, a coordination-number-based variable, CN, was used as one coarse variable to describe the association and dissociation of cations and DNA. CN is defined as the average number of Na+ ions associated to atom N7 on the guanine, the representative atom of the major groove (blue spheres shown in Figure 1A), with a cutoff of 4.0 Å.19 Another coarse variable, the difference in the root-mean-square deviations (ΔRMSD),34, 53, 54 was chosen to characterize the DNA conformational transition from its B form to its A form. Here, ΔRMSD has proven to be effective in describing DNA B-to-A transition.34 The DNA categories can be simply divided according to the range of ΔRMSD, B-form (ΔRMSD = [-5, -3] Å), transformation stage (ΔRMSD = [-3, +3] Å), and A-form (ΔRMSD = [+3, +5] Å). ΔRMSD = +3 Å can, therefore, be deemed as a reference value of B-to-A transition. CHARMM and AMBER are the two main force fields for DNA modeling, showing different ability to describe A-DNA.55-57 In light of previous studies, CHARMM force field can stabilize A-DNA, while, AMBER force field favors the B-form.55-57 Lai and Schatz have suggested that an isolated A-DNA cannot be stabilized by AMBER bsc1 force field even at a high-ethanol concentration.58 To choose an appropriate force field for simulations, two free-energy calculations were performed at high concentration of ethanol. As shown in Figure 2B and C, the most stable structure is the B form for the AMBER, and the A form for the CHARMM force field. The experimental result, however, indicates that A-DNA is the favorable conformation in an 80% ethanol solution.9 Thus, the CHARMM force field appears to 7



perform better than the AMBER force field to stabilize A-DNA. Previous work suggests that A-DNA is not stable when using the AMBER force field, owing to an incorrect description of the sugar pucker transition between north- and south-conformation.59 To describe DNA conformations accurately in different environments, additional improvements of the DNA force fields are necessary, for instance, in the form of a grid-based angular correction, in the spirit of CMAP corrections for peptides and proteins.60,

61

In the present study, the discussions

hereafter are based on the CHARMM force field.

Figure 1. (A) Snapshot of DNA in an 80% ethanol solution obtained from the 50-ns MD trajectory. Free-energy landscapes characterizing the B-to-A transition in an 80% ethanol solution using (B) AMBER bsc1 force field, (C) CHARMM36 force field.

Free-energy Profiles at Different Concentrations of Ethanol Three free-energy landscapes mapped by meta-eABF are depicted in Figure 2A-C. Figure 2D shows the one-dimensional profiles as a function of ΔRMSD along 8


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the least free-energy pathway. In pure water, the most stable structure is the B form. There is, however, no local minimum in the range of ΔRMSD from 0 to +4 Å, indicating that the A form hardly exists in this environment. In a 60% ethanol solution, a broad range of low free energies is covered between the A and the B form, in good agreement with the experimental result that B-to-A transition occurs in an environment containing about 60% ethanol.9 As described in Figure 2C, the most stable structure is the A form in an 80% ethanol solution, without local minimum in the range of ΔRMSD spanning from -4 to 0 Å. The B form is, thus, unlikely to exist in this environment of high alcohol content. In addition, the average number of Na+ ions associated to DNA increases along with the change of ethanol concentration. It can be concluded that addition of ethanol does not only promote association of cations with DNA, but also induces the B- to A-DNA transition.

9



Figure 2. Free-energy landscapes describing the B- to A-DNA transition in (A) 0%, (B) 60%, (C) 85% ethanol (ETOH). (D) One-dimensional profiles as a function of ΔRMSD along the least free-energy pathway. The Motion of Cations along with the B-to-A Transition To delve further into the mobility of the cations, the variation of the average number of Na+ ions associated to DNA was analyzed (see Figure 3 and Figure S2-4 of the SI). As depicted in Figure 3A, for the most stable structure in pure water corresponding to ΔRMSD = -3.2 Å, the number of cations around the minor groove 10


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and the backbone is more than that around the major groove. However, in a 60% ethanol solution (see Figure 3B), cations preferentially aggregate around the major groove and the backbone in a very shallow region of the free-energy landscape, corresponding to values of ΔRMSD ranging from -2 to +4 Å. In addition, the number of cations decreases in the minor groove and increases around the backbone along the B- to A-DNA transition, indicating that the motion of cations from the minor groove towards the backbone induces the conformational transition. As described in Figure 3C, the directed mobility of cations was also found in an 80% ethanol solution. For the most stable structure in 80% ethanol, which corresponds to ΔRMSD = +3.3 Å, cations preferentially aggregate in the major groove and near the backbone. We can, therefore, propose that the movement of the cations towards the backbone modulates the B- to A-DNA transition. Moreover, in light of the percentage of water molecules around DNA in Figure 3D-F, the directional motion of water was found, while not as distinct as that observed for cations. The motion of cations accompanies the influx of water, showing a synergistic effect.

11



Figure 3. The variation of average number of Na+ ions associated to DNA as a function of ΔRMSD in (A) 0%, (B) 60% and (D) 80% ethanol solution. The variation of the percentage of water molecules associated to DNA as a function of ΔRMSD in (E) 0%, (F) 60% and (G) 80% ethanol solution. The Changes of DNA Microenvironment at Different Concentrations of Ethanol The behavior of the water molecules and of the cations is relevant to ethanol concentration. To investigate the dynamic properties of the microenvironment around DNA, three equilibrium simulations were carried out using the initial configurations corresponding to the global minimum, namely ΔRMSD = -3.2 Å (B-form), 2.8 Å (A-form), and 3.3 Å (A-form) in 0%, 60%, and 80% alcohol solutions, respectively (see Figure 4D, F and G). It is worth noting that a chemical equilibrium was found at 60% ethanol from the free-energy calculation, in which the B and the A form can be 12


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easily interconverted. An additional simulation starting from the B-form (ΔRMSD = -1.5 Å) in 60% ethanol was performed (provided in Figure 4E), as a comparison of the different microenvironments of B- and A-DNA at the same ethanol concentration.

Figure 4. The radial distribution functions (RDFs) of cations relative to the (A) major groove, (B) backbone and (C) minor groove. The snapshots of the stable structures of DNA and cations in the first hydration shell in the low-energy basins in 0% (D), 60% (E for B-form, and F for A-form), and 80% (G) ethanol solution.

To describe the distribution of the water and cations, the radial distribution functions (RDFs) of the cations and the water molecules relative to DNA at three distinct ethanol concentrations are reported in Figure 4 and S5. For those cations 13



closest to the major groove and to the backbone of DNA (see Figure 4A and B), the heights of the first peaks increase sharply as more ethanol is added, while an opposite trend is observed for the minor groove (see Figure 4C). Moreover, as described in Figure 4B, the RDFs of the cations around the backbone of the A form are much higher than those for cations around the B form in a 60% ethanol solution. It can be inferred that the mobility of the cations towards the backbone promotes B- to A-DNA transition. The RDFs of those water molecules lying around DNA show an overall trend, whereby the height of the first peaks increases as more ethanol is added to the solution (depicted in S5). To investigate further the effect of the water molecules on the B- to A-DNA transition, the mobility of water was analyzed. As depicted in Figure 5A, the mean-square deviations (MSD) for water molecules was measured in different environments. For pure water, the diffusive motion is much faster than that in ethanol. To understand the behavior of interfacial water around DNA, their residence times in the first hydration shell have been evaluated in Figure 5B. Here, the statistics of residence time of water only includes the water residing in the first shell of hydration for more than 100 ps. Our results show that the hydration water molecules in solutions at high-ethanol concentration are less mobile compared to pure water, and exhibit a typical glassy character. Interestingly enough, as shown in Figure 5B (the red bars), the water mobility around the A and the B forms is different for the 60% ethanol computational assay. Water around the B-DNA is more mobile than around the A 14


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form. Detailed analysis as depicted in Figure 5C shows that the percentage of glassy water molecules around the major groove and the backbone, with respect to all the water in the first shell of hydration, increases with the addition of ethanol. The 60% ethanol computational assay shows the same trend. It can, therefore, be inferred that the increase of glassy water around the major groove and the backbone promotes Bto A-DNA transition.

Figure 5. (A) The MSD time evolution of water molecules. (B) The percentage of water molecules that reside in the DNA first hydration shell for more than 100 ps. (C) The percentage of water molecules that reside around major, minor groove and backbone of DNA for more than 100 ps.

CONCLUSIONS In the present contribution, two-dimensional free-energy calculations have been performed to uncover the role of the microenvironment in the B to A-DNA transition in aqueous solution, at different ethanol concentrations. Taking advantage of a 15



carefully chosen transition coordinate and force fields, we examined the dynamic properties of the microenvironment along with the conformational transition of the DNA sequence at the atomic level. Our results present that cations move from the minor groove to the backbone as ethanol is added to the solution, promoting the B to A-DNA transition. Moreover, the glassy hydration water around the backbone and the major groove is shown to also modulate this transition. The variation of DNA microenvironment accompanying with the conformational changes of the latter is described visually from the two-dimensional landscapes, expounding the effect of the distribution and mobility of water molecules and of cations on the B-to-A transition from a free-energy standpoint. Moreover, understanding the dynamic nature of the DNA microenvironment helps reveal the mobility of water and cations in transcription processes.3 There are still many other things to do in the future. For example, it is in principle possible to quantitatively investigate the effect of microenvironment on the DNA folding by free-energy calculations. ASSOCIATED CONTENT Supporting Information The following files are available free of charge. The structures of A- and B-DNA. The variation of average coordination number of

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water and cations with DNA along the transition coordinate. The RDFs of water molecules relative to DNA.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (W.C.) OICID ORCID of Hong Zhang: 0000-0002-3303-5109 ORCID of Haohao Fu: 0000-0003-0908-0046 ORCID of Xueguang Shao: 0000-0001-5027-4382 ORCID of François Dehez: 0000-0001-8076-6222 ORCID of Christophe Chipot: 0000-0002-9122-1698 ORCID of Wensheng Cai: 0000-0002-6457-7058 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT The authors acknowledge support from the National Natural Science Foundation of 17



China

(21773125),

the

Natural

Science

Foundation

Page 18 of 25

of

Tianjin,

China

(18JCYBJC20500), the Centre National de la Recherche Scientifique through an integrated program of scientific cooperation (PICS) with China, and the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (Second Phase) under Grant U1501501. H. Z. gratefully acknowledges the financial support from China Scholarship Council (No. 201806200074).

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Changes in Microenvironment Modulate the B- to A-DNA Transition

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