B-DNA Conformational Transitions in

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B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules

Free Energy Profiles for A-/B-DNA Conformational Transitions in Isolated and Aggregated States from All-Atom Molecular Dynamics Simulation Cheng-Tsung Lai, and George C. Schatz J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b04573 • Publication Date (Web): 01 Aug 2018 Downloaded from http://pubs.acs.org on August 7, 2018

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The Journal of Physical Chemistry

Free Energy Profiles for A-/B-DNA Conformational Transitions in Isolated and Aggregated States from All-atom Molecular Dynamics Simulation Cheng-Tsung Lai† and George C. Schatz*,† †

Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States

ABSTRACT: In ordinary aqueous solution, B-DNA is the major structural form of DNA. After the addition of ethanol, DNA is thought to be aggregated/condensed in the A-form structure. However there is uncertainty as to whether the Bto-A conformational change is connected to the aggregation/condensation steps. In this study, we performed all-atom molecular dynamics simulations and calculated the free energy surface involved in the A/B conformational transition for isolated and aggregated Dickerson–Drew dodecamers (DDD) in water and 85% ethanol environments. We found in the case of an isolated DDD, the overall free energy profile is entirely downhill to give the B-DNA conformation in both water and 85% ethanol. However, in the aggregated state and 85% ethanol environment there is a free energy minimum associated with the A-DNA region in addition to the global B-DNA minimum, and there is a ~3 kcal/mol free energy barrier to the A-to-B conformational change. The molecular dynamics results suggest that aggregation of DNA is essential for forming A-DNA.

Introduction

superlattice crystals that can be formed using DNAfunctionalized nanoparticles have been shown to exhibit reversible contraction and expansion by switching to ethanol and then water solutions, respectively.13 Here it is thought that DNA might be aggregated/condensed after the addition of ethanol. And several experimental studies have suggested that the formation of A-DNA is connected to aggregation/condensation steps.14-15 On the other hand, some studies have suggested that aggregation/condensation is not necessary.16-18 A better understanding of the connection between aggregation and the formation of A-DNA as well as the mechanical properties involved in the A/B conformational transition is therefore crucial for understanding the properties of DNAfunctionalized nanoparticles.

DNA plays significant roles in biology as it carries the genetic information of all known living organisms. Understanding the dynamics of DNA and its interactions with other molecules becomes crucial for the studies of gene activation, gene regulation, and downstream protein expression, etc. DNA structure is often found to be strongly coupled to its local environment. In ordinary aqueous solution, the right-handed helical structure BDNA is the predominant form of dsDNA, while A-DNA is only found in special conditions, such as when the DNA is bound to certain proteins; or under dehydrating conditions that can include certain crystalline forms or with the addition of ethanol.1-4 In addition, under high salt conditions, B-DNA can convert to Z-DNA, which is a lefthanded helical zig-zag conformation.5 Understanding the conformational changes between A/B DNA, and B/Z DNA is therefore an important topic. Particularly, the B-to-A transition is very important for living organisms as the compact A-form DNA not only prevents UV damage but also involves in binding with RNA and protein.4, 6-8 The Bto-A transition depends on various factors such as nucleotide composition, ion type and concentration, humidity, etc. High GC content is known to stabilize A-DNA conformations and to assist the B-to-A transition.9-11 The less hydrated Na+, K+, Cs+ ions also help the B-to-A transition, while the more hydrated Li+ and Mg2+ ions prevent the Bto-A transition.12

Because of experimental difficulties, most of the available DNA structures are from X-ray crystallography studies. The lack of reliable DNA dynamics data at the atomic level impedes our understanding of the structural flexibly of DNA in different metastable states. The utility of molecular dynamics (MD) simulation in studying biomolecular dynamics and quantifying the interactions between molecules has been routinely demonstrated over the years as a result of significant improvements in force fields and the rapid growth of computational power.19 Therefore, MD simulations have become one of the most important approaches for studying DNA dynamics in the last two decades.20

There have now been several studies in which A/B-DNA conformational changes have been used as a way to alter the properties of biomimetic nanomaterials. For example,

The aim of this study is to understand whether the aggregation of dsDNA is connected to the formation A-DNA. We performed all-atom MD simulations to model the A/B

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transition and calculated the relevant free energy profile, here considering the Dickerson–Drew dodecamer (DDD) dsDNA, which is one of the best known DNA structures. As components of this study we have examined both isolated and aggregated DDD in both pure water and 85% ethanol/ 15% water environments. Based on the simulated results, we show that aggregation of DDD is essential for observing stabilized A-form DNA. Methods System setups. The canonical A and B form of the Dickerson–Drew dodecamer (DDD) DNA d(CGCGAATTCGCG)2 were generated using Nucleic Acid Builder (NAB).21 The isolated and aggregated DDD models are shown in figure 1. (We will use the terms “condensed” and “aggregated” to mean the same thing in this paper.) The AMBER bsc1 DNA force field (which improves on previous AMBER force-fields) was used for all-atom MD simulations.22 Each system was solved in a truncated octahedral box with TIP3P water or 85% ethanol/15% TIP3P water. The shortest distance from the DNA to the edge of the box is 12 Å. The ethanol force field (also derived from AMBER, and therefore consistent with the DNA force field) was taken from the literature.23 Na+ ions were added to neutralize the charge using the Joung-Cheathem model.24 Each system was equilibrated as follows. First, the system was minimized with 1000 steps of steepest descent. Then, the system was gradually heated from 0 to 100 K in 200 ps under constant volume condition using Langevin dynamics with a collision frequency of 1 ps−1. Next, the system was gradually heated from 100 to 300 K in 400 ps under constant pressure (1 atm) condition. A 10.0 kcal mol−1 Å−2 Cartesian restraint was applied on the DNA during the equilibration steps. After the heating steps, a production run under NPT condition was initially performed with 1 kcal mol−1 Å−2 Cartesian restraint on DNA for 100 ns, followed by a 400 ns unrestrained run. Two independent runs were performed for each system and the results are similar. Therefore, only one run’s results are presented here. All MD simulations were performed using sander, or CPU and GPU versions of pmemd in Amber 16.25-27 A-to-B DNA Sampling. To obtain continuous structures between A- and B-DNA, we performed a partial nudged elastic band (PNEB) simulation with the equilibrated structures (last snapshot of 100 ns restrained MD results) as the two endpoint structures.28 The simulation procedure, which involves simulated annealing steps, was adopted from previous studies.29-30 A spring force constant of 300 kcal mol-1 Å-2 was applied to the whole DNA molecule, except for the hydrogen atoms. Umbrella Sampling and Potential of Mean Force. RMSDs referenced to canonical A and B DNA were used as the reaction coordinates for umbrella sampling. The umbrella sampling windows were chosen to have a 0.5 Å interval.

Figure 1. DNA models used in this study. (A) Isolated DDD and (B) Aggregated DDD. In the aggregated DDD, the distance between the center DDD and the other four adjacent DDDs is ~23 Å.

Initial structures at specific windows were extracted from the PNEB trajectories with distance values closest to the respective window values. A 5 ns MD simulation under the NPT ensemble at 300 K was performed for each window. The weighted histogram analysis (WHAM) approach was used to generate the potential of mean force (PMF) from the umbrella sampling results.31-32 The first 1 ns results were treated as equilibration and excluded from the WHAM analyses. Data Analysis Trajectories were analyzed using cpptraj.33 Plots and structure snapshots were generated with matplotlib and VMD, respectively.34-35 Results and Discussion To understand whether aggregation of dsDNA can assist in the formation of A-DNA, we chose the Dickerson– Drew dodecamer (DDD) system as it is a classic nucleotide system with well-established experimental and simulation data. We then built an “isolated” double stranded DDD structure, as well as an “aggregated” structure consisting of 5 double stranded DDDs (Figure 1). In the aggregated DDD model, the distance between the center DDD and the other four DDD’s is ~23 Å, which is the

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The Journal of Physical Chemistry nearest neighbor distance for DNA. To understand the dynamics of DDD in isolated and aggregated states in water and ethanol, we performed standard MD simulations starting from canonical A- and B-form DDD in water and 85% ethanol for both isolated and aggregated DDD. Then we used an enhanced structure sampling simulation, PNEB, to obtain continuous structures between A- and B-DNA, followed by an umbrella sampling approach to reveal free energy profiles.

ment, when DDD starts in A-DNA, it remains in that conformation for ~150 ns before transforming to B-DNA (Figure 2B top). When the simulation is started with the B-DNA conformation, similar to the water case above, the DDD maintains the B-DNA conformation and there is no transition to A-DNA conformation (Figure 2B bottom). These results are unsurprising as a previous study demonstrated that A-form DDD is stable in 85% ethanol for about 200 ns, while a spontaneous A-to-B-form transition is found in water.22

Unrestrained MD simulation with isolated DDD. To understand the dynamical properties of isolated DNA, we performed individual unrestrained MD simulations starting from canonical A- and B-DNA, both in water and 85% ethanol. To make the counter ions well equilibrated, we performed 500 ns MD simulations starting with 100 ns restrained MD (restraints on DNA only), followed by 400 ns unrestrained MD. To quantify the dynamical properties of DNA, we measured the root-mean-squaredeviation (RMSD) of the DNA from canonical A-DNA and B-DNA for a simulation starting from the A-DNA structure in the water. The average RMSD values after release of restraints are ~5.2 Å and ~2.0 Å, respectively (Figure 2A top). It is worth noting here that the DDD crystal structure’s RMSD values, referenced to canonical A-/BDNA are 5.9 Å and 1.3 Å, respectively (using PDB ID: 1BNA). Therefore, the ~2.0 Å deviation from the canonical B-DNA structure can still be treated as B-form DNA. This result suggests that the A-form DDD is an unstable conformation in water, therefore it transfers to B-form DDD after release of restraints. For the case where we start with B-DNA, the RMSD value, referenced to B-DNA is maintained at ~2.0 Å after releasing restraints, demonstrating that DDD maintains a B-form DNA structure in water (Figure 2A bottom). Combining the above A- and B-form started simulations, we can conclude that B-form DNA is the stable structure in water. In 85% ethanol environ-

Since B-DNA can transfer to A-DNA in ethanol solution, it is of interest to know if we can model the B-to-A transition by MD simulations. The B-to-A transition has been shown to be sequence-dependent such that high GC content dsDNA is able to maintain the A-form structure.9-11 The GC content of DDD is about 67% and some studies have been able to capture the B-to-A conversion for DDD in high salt condition or by scaling the charge of water.3637 In our study, we do not see the B-to-A transition in 85% ethanol even if we extend the simulation to 1 µs (Figures S1). Nevertheless, based on our best knowledge, we do not find that any study has successfully modeled the B-toA transition for DDD in ethanol solution by regular MD simulation without tuning the force field or implying an enhanced sampling technique. Very recently a study using the AMOEBA polarizable force field observed the Bto-A transition under 90% ethanol and 328 K condition, but the DDD under these circumstances was unstable and it denatured after about 300 ns.38 This led us to speculate that the aggregation of dsDNA should stabilize the dsDNA structure. To study this, we built an aggregated DDD dsDNA model wherein the center dsDNA DDD is surrounded with other four dsDNA DDDs (Figure 1B). We then performed the same simulations for the aggregated DDD (see below). Unrestrained MD simulation with aggregated DDD. Next, we performed the same simulations for aggregated DDD. For simulations that started with both A- and B-form structures in water, the aggregated DDD dispersed after releasing the restraints (Figures 3). Because of this collapse of the aggregated conformation, each DDD loses its strong interactions with other DDDs. In this situation, the center DDD acts like an isolated DDD. This suggests that the spontaneous B-to-A transition will also happen in this dispersed system. And indeed, the RMSD values of the center DDD show that A-DNA spontaneously transfers to B-DNA after releasing the restraints (Figure S2). These results reinforce the statement that B-DNA is the stable structure in water solution. In addition, dsDNA is less likely to form an aggregated conformation in water.

Figure 2. RMSD of unrestrained MD simulations. (A) in water and (B) 85% ethanol. The top and bottom plots are simulations starting from A-DNA and B-DNA, respectively. Blue and red lines represent RMSD referenced to A and B DNA respectively.

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Figure 3. Snapshots of aggregated DDD in water. (A) Simulation starting from A-DNA and (B) B-DNA. After releasing of restraints on the DNA, the aggregated DDD is dispersed.

In contrast to this, the DDD remains an aggregated structure after 500 ns in simulations with the 85% ethanol environment (Figure 4). Indeed, based on the RMSD, we find that the center DDD remains as A-form after 5oo ns simulation for the A-DNA started structure, while B-DNA remains as B-DNA for the B-DNA started simulation (Figure S3). We extended the simulation time to 1 µs and found that the cluster of five DDDs exhibited a similar aggregated form with the center DDD remaining in the Aor B-form (Figure S4). These results suggest that aggregation of DDD in 85% ethanol can assist in maintaining ADNA conformations. In addition to the center DDD, we also measured the RMSD for the other four DDDs for the A-DNA started simulation and found that two of them transferred to B-DNA. It appears that the center DNA maintains A-form more easily than the rest because the Na+ ions that interact with it are mostly associated with phophates and are therefore more immobilized than Na+ ions near the other DDDs.13 These trapped Na+ ions are able to assist DNA to maintain A-form. Free Energy profile of isolated DDD. Because a free energy profile can provide both thermodynamics and kinetics information, we next calculated the free energy profile for the A/B transition for both isolated and aggregated DDD in water and in 85% ethanol. To get a free energy profile along the transition between A/B DNA, we used an enhanced sampling approach, the PNEB simulation, to sample continuous structures between A/B DNA, followed by umbrella sampling. We chose the RMSD referenced to canonical A and B as the reaction coordinates in the umbrella sampling. Therefore, our free energy profile will cover the landscape relative to A and B conformations in

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Figure 4. Snapshots of aggregated DDD in 85% ethanol. (A) Simulation starting from A-DNA and (B) BDNA. DDD maintains aggregated form after releasing of restraints.

the X and Y axis, respectively, of the plots we present. Based on the unrestrained MD simulation results shown above that the transformation of A-DNA to B-DNA takes place spontaneously in water and in ~150 ns in 85% ethanol, we hypothesized that the global minimum state of the free energy profile should fall in the B-DNA conformation in both water and 85% ethanol cases. The free energy profiles of isolated DDD in water and 85% ethanol are shown in figure 5. In water, the global minimum is in the region having ~5.0 Å and ~2.0 Å RMSD away from the canonical A-DNA and B-DNA, respectively. In the 85% ethanol, the free energy landscape is relatively flat compared to that in water. The lowest energy position is also found at (X, Y) = (5.0, 2.0). To get the free energy difference between A/B DNA, we have to define the ADNA and B-DNA region on the plot since the RMSDs are referenced to the canonical DNA forms. For the B-form DNA, this is relatively easy since the global minimum region (5.0, 2.0) should be the desired region. For the Aform DNA, we found a trajectory in the (2.0, 6.0) region that shows the A-form conformation. To verify whether the structures at (2.0, 6.0) and (5.0, 2.0) in figure 5 are A-

Figure 5. PMF of A/B DNA transitions in the case of isolated dsDNA. (A) In water and (B) In 85% ethanol.


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The Journal of Physical Chemistry and B-DNA, respectively, we measured the C1’-C1’, Zp, inclination, and rise, which are the common descriptors used to distinguish A-/B-DNA. Based on these measurements, the structure taken from the (2.0, 6.0) region exhibits an A-DNA conformation (Figure S5B), while the structure taken from the (5.0, 2.0) region is a B-DNA conformation (Figure S5A). If we treat the (2.0, 6.0) and (5.0, 2.0) regions as the A- and B- DNA, respectively, the overall A-to-B free energy landscape is a downhill process for both the water and 85% ethanol cases. The free energy difference between A-/B-DNA in water and 85% ethanol are ~13 and ~3 kcal/mol, respectively. The steep free energy landscape along the A-to-B transition in water explains why the A-DNA suddenly transforms to B-DNA after releasing the restraints. In contrast, the flat free energy landscape of the 85% ethanol result implies that starting the simulation in the A-DNA configuration samples more A-DNA conformations before transferring to B-DNA. By incorporating the RMSD values measured from the above unrestrained MD simulations, we can see that the majority of population falls in the B-form region in the water environment (Figure S6). On the contrary, the free energy landscape is flatter in 85% ethanol, therefore we observe some population in the A-DNA region and some along the A-to-B path (Figure S7). The free energy profiles therefore provide useful information why the A-to-B transition in water happens spontaneously but has a 100~150 ns time lag in 85% ethanol. Free Energy profile of aggregated DDD. Based on the unrestrained MD simulation results shown above, where simulations starting in A- and B-form aggregates in the 85% ethanol environment maintain A- and B-form, respectively after 1 µs, we speculated that the free energy profile will differ from those above for isolated DDD (Figure 5). In particular, we hypothesized that the simulation of A-DNA in 85% ethanol will have a local free energy minimum, with a free energy barrier preventing Ato-B conformational changes. In the water environment, we assumed the results of aggregated DDD would be similar to the isolated DDD case since the DDD disperses during the unrestrained MD simulations. Therefore, we only calculated the free energy profile in 85% ethanol solution. Figure 6 shows the free energy profile of aggregated DDD in 85% ethanol. The global minimum is in the B-DNA region. In addition, there is a local minimum at (2.0, 6.0), corresponding to the A-DNA structure. Unlike the isolated DDD case where the A-form to B-form landscape is entirely downhill, Figure 6 shows a ~3 kcal/mol free energy barrier that should stabilize the A-form. In addition, the B-to-A free energy barrier is ~6 kcal/mol, which is twice that for the isolated DDD case shown above. By mapping the RMSD values measured from the above unrestrained MD simulations to the PMF, we see that simulations starting from A-DNA only sample the local mini-

Figure 6. PMF for A/B DNA transitions for aggregated DDD in 85% ethanol.

mum region at (2.0, 6.0) (Figure S8A). The ~3 kcal/mol free energy barrier seems to be able to trap the system, at least on the µs timescale based on our results (Figure S4). In the next section we discuss why this combination of barrier and time scale is possible. For simulations starting from B-DNA, all the snapshots fall in the B-form region as expected (Figure S8B). Thus the free energy profiles explain the unrestrained MD simulation results. In summary, we observed that DDD forms a stable B-form in water solution from both isolated and aggregated states, but in 85% ethanol solution, although B-form DDD is the most stable structure, aggregation allows the Aform DNA conformation to be metastable, at least on the ~1 µs timescale. Simulation Limitations. In this study, to generate the free energy profile for the A-/B-DNA transition we used the RMSD as the reaction coordinates for the umbrella sampling. One of the simulation limitations is that the sampling might not be adequate for high RMSD values because this region includes a broader distribution of possible structures that might not even be representative of Aor B- form duplexes. To overcome this, we used two coupled reaction coordinates to restrain high RMSD regions: when the RMSD referenced to A-DNA increases, the RMSD referenced to B-DNA simultaneously decreases. Therefore, the free energy profile is dominated by the diagonal in Figure 6. Based on comparing 3 to 5 ns PMFs for isolated DDD in the water, 5 ns umbrella sampling seems to be adequate for the DDD system (Figure S9). A second simulation limitation is that we only considered the diagonal path in the PMF. It is possible that the A-toB conformational change has a different path. For instance, there could be an off-diagonal path, in which only a fraction of the nucleotides are transformed at any point. Future studies that combine global and local structural



transitions will help better understand this issue. Last but not least, we used potential of mean force to calculate the free energy based on the defined reaction coordinates. It is always possible that these reaction coordinates cannot represent the transition path seen in a standard MD simulation due to correlations between coordinate motions that are not sampled by the RMSD. Therefore, the results of the PMF analysis are mostly of qualitative usefulness. Given that the ~µs timescale seen in the MD simulation is expected to have a barrier of 7-8 kcal/mol it seems likely that the ~3 kcal/mol barrier in the PMF is underestimated. A more precise definition of reaction coordinates is therefore desirable. Conclusions DNA can be aggregated/condensed or even precipitated after the addition of ethanol. It has been suggested that the formation of A-DNA is coupled with the aggregation/condensation steps, but some studies suggest that aggregation/condensation may not be a necessary process. In this study we performed all-atom MD simulations to model the A-/B-DNA transition and we calculated the free energy profile for the isolated and aggregated Dickerson–Drew dodecamer (DDD) dsDNA in both pure water and 85% ethanol environments. By comparing the results from isolated and aggregated DDD, we observed significant differences in free energy profiles. We found that for isolated DDD, the A-to-B transition is a downhill transition in both water and 85% ethanol environments, with free energy changes of -13 and -3 kcal/mol, respectively. When the simulation was started in the aggregated state and water environment, the aggregated DDDs dispersed after releasing the restraints. In contrast, aggregated DDD was stable after 1 µs simulation in 85% ethanol. In the aggregated state there is a local free energy minimum in the A-DNA region for 85% ethanol, and a ~3 kcal/mol free energy barrier prevents the A-to-B transition. As a result, the aggregated state stabilizes the A-form in 85% ethanol. Since our study has focused on the global A/B transition, further studies that combine local and global structure transitions will help us to develop a more complete understanding of the DNA conformational changes. We should note that the present results provide a better understanding of the structural changes recently observed in DNA superlattices in the presence of ethanol.13 In these superlattices, the DNA has a high density close to the gold nanoparticles, so although it will be B-form in the water environment where the superlattices are synthesized, the present results show that it will easily convert to A-form when sufficient ethanol is added.

ASSOCIATED CONTENT Supporting Information. Additional figures. This supplemental document is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author * G.C. Schatz: [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT This research was supported by NSF grant CHE-1465045 and by the Center for Bio-Inspired Energy Science (CBES), an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Basic Energy Sciences, under award DE-SC0000989. Computational time was provided by the Quest High-Performance Computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology.

ABBREVIATIONS DDD, Dickerson–Drew dodecamer; PMF, potential of mean force; PNEB, partial nudged elastic band; RMSD, root mean square deviation; WHAM, weighted histogram analysis

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