BI BII Substate Transitions Induce Changes in the Hydration of B-DNA

J. Phys. Chem. B 2001, 105, 10379-10387

10379

BI h BII Substate Transitions Induce Changes in the Hydration of B-DNA, Potentially Mediating Signal Transduction from the Minor to Major Groove Wolfgang Flader, Bernd Wellenzohn, Rudolf H. Winger, Andreas Hallbrucker, Erwin Mayer, and Klaus R. Liedl* Institute of General, Inorganic and Theoretical Chemistry, UniVersity of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria ReceiVed: October 31, 2000; In Final Form: July 26, 2001

The EcoRI DNA dodecamer d(CGCGAATTCGCG)2 was investigated by a 10 ns molecular dynamics simulation. The BII substate distribution within one strand is shown to give an alternating pattern and thus avoids two successive phosphates remaining simultaneously in the BII substate. Increased BII population (BI/ BII ratio of 3.7 compared to 9.2 in a previous simulation) was observed by employing improved force field parameters derived recently by Cheatham et al. [Cheatham, T. E., III; Cieplak, P.; Kollman, P. A. J. Biomol. Struct. Dyn. 1999, 16, 845-862]. Furthermore, BI h BII conformational transitions are shown to correlate with the hydration pattern of the phosphate group, the sugar oxygen, and the minor and the major groove. Therefore, BI/BII substates can act as an additional conversation tool to transfer binding information from a drug ligand in the minor groove to a protein binding site in the major groove.

1. Introduction Hydration and dynamical behavior of DNA play a decisive role for its biological function.1-12 Especially the interconversion between the conformational substates of B-DNA, BI and BII, may participate significantly in ligand binding within the backbone phosphate groups, which has been shown to be important in numerous investigations.2,9,10,12-23 In the BI state the corresponding and ζ angles derived from X-ray structures are between 120-210° (trans) and 235-295° (gauche-), respectively; for BII lies between 210° and 300° (gauche-) and ζ between 150° and 210° (trans).24 So a BI h BII interconversion represents a small but significant reorientation of the charged phosphate group of the DNA backbone. Figure 1 shows a part of the DNA dodecamer with one phosphate group in both the BI and BII conformation. The upper picture is a snapshot at 900 ps with the highlighted phosphate in the BII substate; the lower picture is a snapshot at 2100 ps, therein the same phosphate is in the BI state. The EcoRI DNA dodecamer d(CGCGAATTCGCG)2 was subject of numerous experimental and theoretical studies.25-49 The vast amount of data available for this dodecamer and its complexes with different ligands provide an ideal field for comparative investigations regarding structure and dynamics of free and complexed B-DNA. A detailed knowledge of molecular recognition processes between DNA and proteins or small ligands can give insight into the regulation of the expression of genes23,50-67 and therefore explains function and misfunction of regulatory processes in the cell. This knowledge is of crucial importance for the development of strategies and highly selective drugs for the treatment of cancer and viral or microbial diseases.31,35,38,51,54,58,60,68-82 2. Methods Molecular dynamics (MD) simulations provide an excellent tool for the investigation of structure and dynamics of biomolecules in their biologically active form.83-86 Improved param-

etrization of the force fields and description of the long-range interactions using the Ewald summation (implemented in the AMBER program87 in the form of the particle mesh Ewald method88,89) enable MD simulations to provide stable B-DNA trajectories39,90,91 and to supplement experimental data by information of unique space and time resolution. The fast interconversion between the BI/BII substates of DNA, which are assumed to interconvert on the subnanosecond time scale,92-98 allow an exhaustive description of this conformational aspect by computer simulations. This gives an excellent completion to the current experimental methods like X-ray crystallography, and NMR and IR spectroscopy, which provide valuable experimental data as starting information. These experimental methods suffer from crystallization effects or insufficient resolution in time and space, which make a detailed description of the BI h BII substate interconversion behavior very difficult. Nevertheless, they are used to confirm the accuracy of the computer simulations. 3. Computational Details As a starting structure the canonical B-form99,100 of the DNA oligonucleotide d(CGCGAATTCGCG)2 was used. To achieve electroneutrality of the system containing 11 PO4- anions in each strand, 22 Na+ counterions were added using the CION program of the AMBER package. TIP3P101 Monte Carlo water boxes were added to form a solvation box at least 12 Å thick in all directions, resulting in a system of 68 × 45 × 45 Å3 containing 3874 water molecules. The corresponding Γ value (i.e., water molecules per nucleotide) is about 161. The simulation was carried out using the AMBER5102 suite of programs employing the all atom force field103 and the modified parameters from Cheatham et al.104 The simulation protocol was the same as in the work of Winger et al.105 4. Results In the course of the simulation the number of phosphate groups being simultaneously in the BII substate ranged from 1

10.1021/jp004046q CCC: $20.00 © 2001 American Chemical Society Published on Web 10/03/2001

10380 J. Phys. Chem. B, Vol. 105, No. 42, 2001

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Figure 2. Conformational substates as a function of time: The time the respective -angle of the 22 phosphates is in substate BII is marked by a black line/dot. X-axis: Enumeration of the interconverted phosphate groups according to Kopka et al.120 Y-axis: Time (ps).

Figure 1. Part of the DNA dodecamer with one phosphate group in both the BI and BII conformations. In the upper picture (snapshot at 900 ps) the highlighted phosphate is in the BII substate; in the lower picture (snapshot at 2100 ps) the same phosphate is in BI.

to 9. The distribution of the BII substates over the whole dodecamer shows a clear preference of the first and last third of every strand (see Figure 2). The ATTC regions contain very few BII states, especially both of the TpT phosphates stay in the BI state over the whole 10 ns. The time-averaged number of phosphate groups in the BII state of 4.7 corresponds to a BI/BII ratio of 3.7 (about 21% BII). This increased BII population (previous simulations105 showed a BI/BII ratio of 9.2) results from the use of improved force field parameters derived recently from Cheatham et al.104 and gives a completely new picture of the BI h BII interconversion behavior. Although the increased BII population leads to regions with a relatively high concentration of this substate, the distribution of BII states within one strand shows an alternating pattern avoiding two successive phosphates remaining simultaneously in the BII substate. For phosphates preferentially in the BII substate (P5, P11, P17, and P23) this anticorrelation with the substate of adjacent phosphates (P4, P6, P10, P16, P18, and P22) results in a mean probability of 0.5% to find a BII-BII sequence. (Phosphates of endstanding base pairs were not considered in this summary because their artificial flexibility may influence the results.)

The complete set of all -angles and their conformation as a function of time is depicted in Figure 2 for the 22 phosphates of the dodecamer’s 22 base steps. As observed in previous investigations,105 analysis of counterions did not show direct correlations between BI h BII substate transitions and dynamics of the sodium ions. For selected phosphates that show a representative BI h BII dynamic (P4, P5, P6, P10, and P11), the occupation with counterions was rather low. The area within 5 Å arround their phosphate oxygens, O1 and O2, was occupied by a sodium ion only 0.8% of the time. Within 5 Å arround the minor groove atoms N3 of G4, A5, A6, G10, and O2 of C11, the mean occupation with counterions was less than 0.7%. Within an 8 Å area of these phosphates and minor groove atoms the mean presence of a sodium ion was 3.9 and 3.3%, respectively. Anyway, also with this increased occupation no correlations with BI h BII substate transitions were observed. This is not in contradiction with the findings of Wilson et al. that minor groove structure and dynamics show direct ion dependence.106 They observed a correlation of minor groove width (which is surely related to BI/BII substates) with ion positions especially in the AATT region of the EcoRI DNA dodecamer. In this part the BII activity is rather low. Therefore, this sequence may be unsuitable for a detailed analysis of possible correlations between BI h BII substate transitions and the mentioned counterion-influenced minor groove width. The correlation between the BI/BII interconversions and sugar puckering and destacking of adjacent base pairs is shown in Figure 3 for the G4-A5 (left column) and G22-C23 base steps (right column). These two representative base steps were chosen because of the high BII amount with very distinct BI h BII interconversions. The -angles are shown as a function of time in pictures a and b, in pictures c and d the destacking of adjacent base pairs is represented by the projected C1′ (sugar carbon attached to the base) distances107 as criterion (Dxy), the sugar puckering of the preceding base is shown in pictures e/i and f/j, respectively, and the one of the following base is in pictures g/k and h/l, respectively. As expected, the BI h BII interconversions show a strong correlation with both the sugar pucker and the destacking of both adjacent base pairs. Thereby, the correlations are stronger for the sugar previous to a phosphate than for the following one. Correlation factors between the BI/ BII substates of the phosphate P5 and sugar puckering of G4 are +0.56 and -0.24 for the amplitude and the angle, respectively. The sugar puckering of A5 shows correlation

BI h BII Substate Transitions in B-DNA

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Figure 3. Substate interconversion of the G4-A5 (left column) and the G22-C23 base step (right column). (a) and (b): -angles as a function of time. (c) and (d): destacking (Dxy) of adjacent residues by using the projected C1′ (sugar carbon attached to the base) distances107 as criterion. Sugar puckering angle of the pseudorotation cycle of the furanose ring in G4 (e), G22 (f), A5 (g), and C23 (h). Pucker amplitude of the furanose ring in G4 (i), G22 (j), A5 (k), and C23 (l).

factors of -0.28 and +0.40 to the substates of the same phosphate P5. In the case of the phosphate P23 the difference is even stronger. The puckering of the previous sugar (G22) correlates with factors of 0.68 for the amplitude and -0.59 for the angle, the respective values for the sugar of C23 are -0.20 and +0.32 (correlation factors were calculated using the corrcoef function implemented in the matlab108 program).

The puckering angle of the pseudorotation cycle of the furanose ring fluctuates around a mean value of about 180° in the BI state and around a mean value of 150° in the BII state. Very seldom and without assignable correlation it changes to a value of about 350° for a few tens of picoseconds by decreasing from the 180° region to about -10° ()350°). The pucker amplitude of the furanose ring fluctuates around a mean value


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Figure 4. Substate interconversion of the G4-A5 (left column) and the G22-C23 base step (right column). (a) and (b): -angles as a function of time. A time dependent hydration pattern is shown by the number of water oxygens closer than the specified distance to the following atoms: within 3.3 Å of N2 of G4 (c) and G22 (d), within 3.1 Å of N3 of G4 (e) and N3 of G22 (f), within 3.3 Å of the phosphate oxygen O1 of P5 (g) and P23 (h), within 3.0 Å of O3′ of G4 (i) and G22 (j), within 3.2 Å of sugar ogygen O4′ of A5 (k) and C23 (l). The different distances were chosen in order to give an optimal representation of the correlations.

of about 0.33 Å in the BI state, and around a mean value of 0.45 Å in the BII state. The destacking reference C1′-C1′ distance between the two adjacent residues, Dxy, fluctuates around a mean value of about 4.8 Å in the BII state, and a broad area with mean values from 2 to 3.5 Å in the BI state. The changes in the hydration of adjacent base pairs in correlation with the BI h BII interconversions are shown in Figure 4 (minor groove, ester oxygen O3′, phosphate oxygen

O1, and sugar oxygen O4′) and Figure 5 (major groove and phosphate oxygen O2). The hydration of some edges of the bases in the minor groove shows a moderate correlation to the BI h BII interconversions: N2 (G4/G22) and N3 (G4/G22) are slightly more hydrated in the BI than in the BII state (pictures c/d and e/f in Figure 4). The hydration of N3 (A5) and O2 (C23) (not shown in Figure 4) is not correlated to the substate interconversions (correlation



Figure 5. Substate interconversion of the G4-A5 (left column) and the G22-C23 base step (right column). (a) and (b): -angles as a function of time. A time dependent hydration pattern is shown by the number of water oxygens closer than the specified distance to the following atoms: within 3.5 Å of O6 of G4 (c) and G22 (d), within 3.5 Å of N7 of G4 (e) and G22 (f), within 3.5 Å of N6 of A5 (g) and N4 of C23 (h), within 3.5 Å of N7 of A5 (i), within 3.1 Å of the phosphate oxygen O2 of P5 (j) and P23 (k).

factor +0.03 and -0.07). The phosphate oxygens O1 and O3′, and the sugar oxygen O4′ show a strong correlation to the BI h BII interconversions: the charged phosphate oxygen pointing toward the minor groove (O1) and the phosphate ester oxygen O3′ are most hydrated in the BI state (pictures g/h and i/j in Figure 4), whereas the sugar oxygen O4′ in this state is less hydrated (pictures k/l in Figure 4). In the major groove the correlations between the hydration of the edges of the bases and the BI/BII substates are as

follows: O6 (G4/G22) and N7 (G4/G22) are more hydrated in the BII substate (pictures c/d and e/f in Figure 5), N6 and N7 (A5) are more hydrated in the BI substate (pictures g and i in Figure 5). The hydration of N4 (C23) (picture h in Figure 5) shows only a poor correlation to the substate interconversions, it is slightly better in the BI state. The base edge of cytosine has only one hydrophilic atom (N4) pointing toward the major groove (compared to N6 and N7 of adenine), so there is one picture missing in the right column of Figure 5. There is a


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TABLE 1: Correlation between BI h BII Substate Transitions and the Hydration Shown in Figures 4 and 5 Represented by the Correlation Factor (Corr), Calculated with a Smoothed Hydration Description Using the Mean Value of 10 ps for Every Stepa minor groove

G4-A5 atom corr

N2 (G4) -0.33

N3 (G4) -0.14

a

O1 (P5) -0.75

O3′(G4) -0.77

O4′(A5) +0.57

O6 (G4) +0.37

N7 (G4) +0.25

minor groove

G22-C23 atom corr

N3 (A5) +0.03

major groove

N2 (G22) -0.62

N3 (G22) -0.18

O2 (C23) -0.07

O1 (P23) -0.77

N6 (A5) -0.48

N7 (A5) -0.57

O2 (P5) +0.40

major groove O3′(G22) -0.82

O4′(C23) +0.48

O6 (G22) +0.58

N7 (G22) +0.63

N4 (C23) -0.18

NA

O2 (P23) +0.45

A positive sign means that the atom is more hydrated in the BII substate; with a negative sign the hydration is better in the BI substate.

moderate correlation with a better hydration in the BII substate for the charged phosphate oxygen pointing toward the major groove (O2) (pictures j/k in Figure 5), although the matches of the changes in the hydration with the BI h BII substate transitions are not as evident as for the phosphate oxygen O1. The correlations of all these changes in the hydration with the BI h BII substate transitions are summarized in Table 1 by a correlation factor calculated between the time dependent -angle and a smoothed hydration description represented by the mean value of 10 ps of the water population within a given distance for every step (correlation factors were calculated using the corrcoef function implemented in the matlab108 program). To give a better insight into the chronology of the observed effects in correlation with the BI h BII substate transitions, Figure 6 shows an enlarged part of the previous pictures for the G4-A5 step. It represents the time period from 1500 to 2500 ps, containing a transition from BII to BI at about 1720 ps and a transition from BI to BII at about 2100 ps (a few trials to change from the BII to the BI substate at about 1580, 2190, 2330, and 2460 ps are too short and do not reach an equilibrated BI substate). The pictures are arranged in the same manner as in Figures 3-5. So the -angle is shown as a function of time in the first row, the left column represents destacking and sugar puckering, and the middle and the right column show the hydration of the minor and the major groove, respectively. For better visibility the hydration herein is represented by the mean value of 10 ps for every step (as used for the calculation of the correlation factor), instead of the single values shown in Figures 4 and 5. The short changes from BII to the BI substate that turn back after a few picoseconds do not have a sufficient effect on the observed parameters to allow a significant conclusion. The transition from BII to BI at 1720 ps initiates the loss of destacking, whereas the changes of sugar puckering began a few tens of picoseconds earlier and are just complete at this time. The transition from BI to BII at 2100 ps is preceded by a slower convergence to the typical values for the BII substate of both destacking and sugar pucker (left column of Figure 6). Changes in the hydration of the minor and major grooves are difficult to correlate exactly to the substate transitions at this resolution (in a detailed view there are strong local fluctuations and in a more global view the graphs are relatively smooth, which makes an unambiguous assignment impossible). For the oxygens of the DNA backbone (phosphate group and sugar) the correlation is more evident and can be summarized in the conclusion that the change in the hydration starts about contemporary with the substate transition and in some cases needs a few tens of picoseconds to reach the new equilibrated state (middle and right column of Figure 6). 5. Discussion The use of improved force field parameters derived recently from Cheatham et al. leads to an increased BII population104

(BI/BII ratio of 3.7 compared to 9.2 in a previous simulation). Despite this relatively high BII population concentrated in the first and the last third of the dodecamer, the BII states within one strand are alternating. This avoids two successive phosphates remaining simultaneously in the BII state, and it confirms the observation of Grzeskowiak et al. that “BII conformations are seldom found at adjacent steps along a chain”.107 The hierarchy of BII forming tendencies predicted in this same work107 was later extended by Winger et al.,105 leading to the conclusion that the BII substate is highly unfavorable only for pyrimidinepyrimidine steps (which are in the BII substate in only 10 of 353 analyzed steps of this type). This is consistent with our simulation where the ATTC regions show only a few transitions to BII for very short periods (see Figure 2). Another observation made on analysis of single-crystal structures of DNA decamers at high resolution107,109 and confirmed later by molecular dynamics simulations of the dodecamer in aqueous solution105 regards the correlation between the BI/BII substates and the destacking of the bases on either side of the phosphate. Our simulation confirms again the rule that destacking is a necessary but not a sufficient condition for an adoption of the BII phosphate conformation. A detailed observation of the destacking (Figure 6: second picture of the left column) shows the fast decrease of this parameter after the transition from BII to BI, whereas the following increase is slower and the typical value for the BII substate is reached before the change from BI to BII occurs. The hydration of the whole B-DNA is influenced by the BI/ BII substate pattern, and the observed changes in the hydration shell are in agreement with spectroscopic data showing BI h BII substate interconversions by IR experiments.44,46 ,110 A detailed analysis of the accessible surface for the hydrogenbonding atoms of the major groove was presented recently by Tisne´ et al.111 They describe an increased accessible surface for most of the O6 and N7 atoms of the guanines in the BII substate, which agrees with increasing hydration of these atoms in the BII substate observed in our simulation (see Table 1). But, their results show also that sometimes the correlation between BI h BII substate interconversions and the accessible surface for a certain atom type can be ambiguous even when the sequence is the same over four base pairs. So one should be careful to derive simple predictive rules from a few data. Instead, these dynamics of the BI/BII hydration may be seen in general as a transfer of this substate information to protein or drug binding sites in the major or minor groove and therefore may give an additional meaning to the sequence dependent BI/ BII behavior.24,112-114 Besides this, such specific movements in the first hydration shell may be able to reduce the thermodynamic penalty for the dehydration of hydrophilic groups and hence support the formation of hydrogen bond contacts in DNA-ligand complexes.



Figure 6. Substate interconversion of the G4-A5 base step in the period between 1500 and 2500 ps. The left column shows details of the pictures in Figure 3 (-angle, destacking and sugar puckering), the middle and the right columns present details corresponding to the left columns of Figures 4 and 5, respectively (time dependent hydration represented herein by the mean value of 10 ps for every step).

While the correlation of the hydration in the major groove with the BI h BII substate interconversions is surprisingly high, in the minor groove only a few of the edges of the bases show a hydration pattern with significant dependence on these substate transitions. Nevertheless, the evident correlation of the hydration

of the sugar oxygen O4′ and the phosphate ester oxygen O3′ (both pointing toward the minor groove) with the BI/BII interconversions allows us to widen the influence of the substate pattern also to the ligand binding sites in the minor groove. Especially changes in the hydration of the phosphate groups

10386 J. Phys. Chem. B, Vol. 105, No. 42, 2001 show a strong correlation with BI h BII substate transitions. These differences in the shielding of the charges of the phosphates may lead to a dynamical behavior of the electrostatic field in the environment of B-DNA, which is responsible for the orientation of ligands in the first steps of complex formation.115 Certainly the phosphate groups of the DNA backbone contribute the major part of DNA-protein contacts not only in the so-called nonspecific DNA-ligand complexes but also in complexes with proteins of high specificity,20,116 and therefore the sequence dependent BI/BII pattern and dynamics may represent an additional tool to increase their sequence specificity. Finally, this dynamical behavior of the B-DNA backbone and the correlated hydration may play a crucial role in the mechanism by which minor groove binding drugs act on the binding site of proteins in the major groove. In a complex with a small drug molecule in the minor groove, the BI/BII substate pattern of B-DNA can be frozen-in in a form completely different from that of the free DNA in solution.117-119 Usually this is a direct consequence of ligand contacts with the DNA backbone phosphates, but partially it may also result from the substitution of water molecules by the ligand and the involved loss of flexibility in the minor groove. This fixed unusual BI/BII pattern leads to the discussed changes in the hydration, and so the electrostatic behavior and the hydration of potential binding sites in the major groove may be influenced also by a minor groove binding drug in relatively rigid DNA tracts where larger structural deviations like bending or changes in the groove width are negligible. 6. Summary and Conclusions A 10 ns state-of-the-art molecular dynamics simulation of the EcoRI DNA dodecamer was performed and analyzed with special attention on BI/BII substates and hydration. The DNA backbone exhibited a highly dynamical behavior with respect to BI h BII interconversions, and only the two TpT steps remained in the BI substate over the whole 10 ns. Despite the high BII population (about 21%) the substate distribution showed an alternating pattern. This avoids BII conformations being found simultaneously at adjacent steps along a chain. The hydration of the whole B-DNA performed a dynamic that is correlated to the BI h BII substate transitions. This proposes a possible additional function of the backbone substates for sequence specific recognition and for signal transductions from minor to major groove. Acknowledgment. This work was supported by a grant of the Austrian Science Fund (grant number P13845-TPH). References and Notes (1) Berman, H. M. Curr. Opin. Struct. Biol. 1994, 4, 345-350. (2) Beamer, L. J.; Pabo, C. O. J. Mol. Biol. 1992, 227, 177-196. (3) Hartmann, B.; Lavery, R. Q. ReV. Biophys. 1996, 29, 309-368. (4) Prive´, G. G.; Heinemann, U.; Chandrasegaran, S.; Kan, L.-S.; Kopka, M. L.; Dickerson, R. E. Science 1987, 238, 498-504. (5) Robinson, C. R.; Sligar, S. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 2186-2191. (6) Egli, M.; Tereshko, V.; Teplova, M.; Minasov, G.; Joachimiak, A.; Sanishvili, R.; Weeks, C. M.; Miller, R.; Maier, M. A.; An, H.; Cook, P. D.; Manoharan, M. Biopolymers 2000, 48, 234-252. (7) Kunkel, T. A.; Wilson, S. H. Nature Struct. Biol. 1998, 5, 95-99. (8) Dickerson, R. E. Nucl. Acids Res. 1998, 26, 1906-1926. (9) Somers, W. S.; Phillips, S. E. Nature 1992, 359, 387-393. (10) Carrondo, M. A.; Coll, M.; Aymami, J.; Wang, A. H.; van der Marel, G. A.; van Boom, J. H.; Rich, A. Biochemistry 1989, 28, 78497859. (11) Gupta, G.; Bansal, M.; Sasiskharan, V. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 6486-6490.

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BI BII Substate Transitions Induce Changes in the Hydration of B-DNA

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