Solution structure of 2¢,5¢ d(G
4
C
4
)
Relevance to topological restrictions and nature’s choice of phosphodiester links
Bernard J. Premraj
1
, Swaminathan Raja
1
, Neel S. Bhavesh
2
, Ke Shi
3
, Ramakrishna V. Hosur
2
,
Muttaiya Sundaralingam
3
and Narayanarao Yathindra
1
1
Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, India;
2
Department of Chemical
Sciences, TIFR, Colaba, Mumbai, India;
3
Department of Chemistry, The Ohio State University, Columbus, OH, USA
The N MR structure o f 2¢,5¢ d(GGGGCCCC) was deter-
mined to gain insights into the structural differences between
2¢,5¢-and3¢,5¢-linked DNA duplexes that may be relevant

the optimization of t opological features might have been a
factor in the rejection of 2¢,5¢ links in preferenc e to 3¢,5¢ link s.
Keywords: structure of 2¢,5¢ DNA; evolution of 3¢,5¢ vs. 2¢,5¢
links in nucleic acids; AB hybrid structure ; restrained base
pair movements; topological restrictions in 2¢,5¢ DNA.
Nature’s selection of 3 ¢,5¢ linkages ( instead of 2¢,5¢ linkages)
in nucleic acids, to encode genetic information, is intriguing.
Thefactthat2¢,5 ¢ links are formed i n a bundance and serve
as a template in nonenzymatic reactions suggest that they
might have been the ancestors of the biotic 3¢,5¢ links, which
could h ave e volved from a pool of 3¢,5¢ and 2 ¢,5¢ links [1].
Nucleic a cids with 2¢,5¢ links satisfy one of the critical
features required for the fidelity of replication, namely that
theyassociatetoformWatsonandCrickbase-paired
duplex structures [2–5], although with weaker affinity than
3¢,5¢-linked DNA strands. However, detailed knowledge
about stereochemistry, polymorphism and topological
properties of 2¢,5¢ DNA duplexes, which may provide
insights into the factors that determine nature’s choice of
sugar-phosphate links from a stereochemical perspective, is
sparse [6–9]. In fact, there are only two reports of NMR
structure determination – one on a 2 ¢,5¢ DNA fragment [10]
and one on a 2¢,5¢ RNA fragment [ 11] – both of w hich
suggest an A-type duplex structure with s ome stereochem-
ical details that differ from genomic DNA and RNA
duplexes. In this context, it is relevant to recognize the
results from recent modeling studies on 2¢,5¢ nucleic ac ids,
which suggest that 2¢,5¢ DNA cannot form a 10-fold
BDNA-like duplex (like 3 ¢,5¢ DNA) without the mandatory
slide (‡ )1.6 A

Biophysics, U niversity of M adras, Guindy C ampus, Chennai-600 025,
India. Fax: + 9 1 4 4 2230 0122,
2
Tel.: + 91 44 2235 1367,
E-mail:
Abbreviations:d(G
4
C
4
), d(GGGGCCCC); LALS, linked atom least
squares; RDC, residual dipolar couplings.
(Received 4 March 2004, revised 30 A pril 2004, ac cepted 21 May 2 004)
Eur. J. Biochem. 271, 2956–2966 (2004) Ó FEBS 2004 doi:10.1111/j.1432-1033.2004.04225.x
solution was incubated in a 55 °C water bath for 16 h and
then lyophilized. The pellet from lyophilization was dis-
solved in 5% NaHCO
3
and purified by FPLC. The collected
peak elution was lyophilized and the sample stored at
)20 °C. NMR samples (0.6 m
M
)ofthe2¢,5¢ DNA fragment
were prepared in 20 m
M
potassium phosphate buffer
containing 0.5 m
M
EDTA and 100 m
M
KCl. For experi-

were recorded with mixing times of 30 and 90 ms at 2 °C.
The DQF-COSY spectrum [16,17] and 2D J-resolved
spectra [18] were recorded in D
2
Ofor
1
H–
1
H coupling
constant estimation. For the various experiments, the time
domain data c onsisted of 2048 c omplex points i n t2 and
300–400 complex points in t 1 dimension. The relaxation
time delay was between 1 and 3 s for the different 2D
experiments.
Experimental restraints
Data processing and analysis were carried out using
VNMR
and
FELIX
packages [ 19] on a Silicon graphics work station.
Based on the relative intensities and build-up, the cross
peaks in the NOESY s pectra (obtained in D
2
O at various
mixing times), are classified as strong, medium-strong,
medium, and weak, and the interproton distances are
restrained, respectively, to the ranges 2–3 A
˚
, 2.5–3.5 A
˚

˚
)
for a syn conformation and r elatively much l onger ( 3.5–
4.0 A
˚
)forananti conformation. Thus, the H8/H6–H1¢
NOE will be very strong, even at short mixing times (such as
60–70 ms) if the glycosyl torsion angle is in the syn domain,
whereas, u nder the sa me conditions, the peak will be nearly
absent for an anti conformation. We observe that G1 has a
syn conformation, while all others are in the anti domain
(spectra presented in Results).
The 2D J-resolved spectra provides precise values of the
J(H1¢–H2¢) coupling constants (Table 1). The observed
coupling constants are very small, indicating that the
sugar geometry b elongs largely to the N domain (in the N
domain this coupling constant is near 0–2 Hz, whereas it
varies between 9 and 10 Hz in the S domain). A common
practice is to consider the sugar geometry as an equilib-
rium mixture of N and S types, and the coupling
constants as weighted averages. However, there are also
reports in the literature [18] where the sugar ring is
believed t o be rigid, and is primarily of a single type, at
least in the interior of the duplex. In the present case, we
observe that the terminal residues, for example, C8 and
G2, where one would have expected greater dynamism,
exhibit very small values ( 1.5Hz) for J(H1¢–H2¢). If one
considers an equilibrium model, for a 10% contribution of
the S domain, the contribution to t he coupling c onstant
would be around 1 Hz. Moreover, it is c lear from the

(Eur. J. Biochem. 271) 2957
equivalent), NCS restraints were imposed to ob tain sym-
metry between the two strands forming the duplex.
Structure calculation
Structure calculation of the iso d(GGGGCCCC) was
carried out using
X
-
PLOR
3.8.5 [21]. The topology and
parameter files w ere appropriately modified t o handle 2¢,5¢
linkages to obtain optimum geometry at the 2 ¢,5¢ phospho-
diester linkage. Ideal A- and B-type duplex models for iso
DNA (possessing helical parameters identical to those of the
canonical ADNA and B DNA), obtained p reviously [9]
using the linked atom least squares (LALS) refinement
approach [22], were used as the starting models for structure
calculation. This is justified considering that the NMR
spectra in water clearly estab lish Watson and Crick b ase
pair formation between antiparallel strands. The model iso
ADNA duplex is characterized by the s ame value of slide,
X-displacement and the helical parameters, as ADNA. On
the other hand, the iso BDNA model, while possessing the
same h elical parameters as BDNA, is distinguished by a
nonzero slide ( ‡ )1.7 A
˚
) and X-displacemen t (‡ )2.5 A
˚
), in
sharp c ontrast to the ideal BDNA that is characterized b y

100 K , at steps of 50 K. During each cooling step the
structures were subjected to 500 fs of molecular dynamics.
Finally, the structures were energy minimized using the
conjugate gradient algorithm. This was followed by a
refinement using the Ôgentle refineÕ protocol, where each of
the structures was subjected to 20 ps of m olecular dynamics
at 300 K. Average coordinates over the last 10 ps of
molecular dynamics simulation were computed and then
refined by conjugate gradient minimization. The NOE
distance restraints, hydrogen bond restraints (given as two
distances per hydrogen bond), and dihedral restraints on the
sugar conformation were applied throughout the entire
calculation with force constants of 50 kcalÆmol
)1
ÆA
˚
)2
,
100 k calÆmol
)1
ÆA
˚
)2
and 300 kcalÆmol
)1
ÆA
˚
)2
, respectively.
NCS restraints w ith a force constant of 300 kcalÆmol

O (data not shown), the melting temperature of the
duplex was seen to be  30 °C.
Tables 2 a nd 3
3
show the chemical shift values for a ll the
assigned sugar and base protons. The stereospecific assign-
ments involving the 3¢ and 3¢¢ protons were based on the
2¢)3¢ and 2 ¢)3¢¢ NOE intensities in the 70 m s NOESY
spectrum. As the H2¢–H3¢ proton separation is shorter t han
the H2¢–H3¢¢ separation, irrespective o f the sugar confor-
mation, the H2¢–H3¢ NOE intensity should be stronger at
shorter mixing times. The relative intensities of the cross-
peaks of the interproton base to sugar NOEs in the NOESY
spectrum (Fig. 3C), at mixing times varying from 70 to
300 m s, indicate that the 5¢-terminal guanine exists in the
Fig. 1. Plots showing the dependence of the 3 -bond coupling constants
(J) on the phase a ngle of ps eudorotation (P).
2958 B. J. Premraj et al. (Eur. J. Biochem. 271) Ó FEBS 2004
syn conformation, while other bases favor t he anti confor-
mation. This is a recurring feature found in 2¢,5¢-linked
dimers [25–27] and oligomers [10,11]. In the crystal struc-
tures o f 2 ¢,5¢-linked dinucleoside monophosphates, the syn
conformation is stabilized by an intramolecular hydrogen
Fig. 2. NMR spectra and the NOESY spectrum. (A) 1D H
2
O
exchangeable NMR spectra of iso d(GGGGCC CC) in 100 m
M
KCl,
pH 7.0, and at 2 °C, showing the imino and amino proton signals. (B)

X
-
PLOR
3.8.5
[21]. Experimental restraints and structure convergence
parameters are listed in Table 4. The convergent structures
are clustered into families: BFI (Fig. 4A) with 39 structures,
and BFII (Fig. 4B) with 20 structures when the starting
model was ideally iso BDNA; and AFI (Fig. 4C) with 85
structures and AFII (Fig. 4D) with 15 s tructures when the
starting model was iso ADNA. Structures represented
by BFI and AFI families (FI) differ considerably in their
overall topologies from the structures represented by BFII
and AFII families (FII). The root mean square devi-
ation (rmsd) b etween FI and FII is greater t han 3 A
˚
, while
it is less than 1 A
˚
for structures within FI or FII. The
structures were selected using standard criteria on the basis
of proper c ovalent geometry, the least number of distance
and dihedral violations, symmetry and low energy.
The duplex model AFI (Fig. 5A), c losely resembles BFI
(Fig. 5 B). T he rmsd between the average structure of AFI
(Fig. 5 A) and BFI (Fig. 5 B) is 0.8 A
˚
. Thus, in spite of the
large rmsd (> 4 A
˚

and )1.62 A
˚
(Table 5), r espectively.
On the other hand, slide for the GC pair at the GC step that
links the G stretch with the C stretch is rather high
()3.3 2 A
˚
).
The nature of the base stacking interaction in the iso
d(GGGGCCCC) duplex, as seen in AFI, is shown in
Fig. 6A. Stacking at the G
2
G
3
and G
3
G
4
steps involves
overlap of t he six-membered ring of one gu anine with the
imidazole r ing o f the adjacent guanine, while there i s only
Table 3 . Chemical s hifts (p .p.m ) f or iso d(GGGGCCCC)
2
exchange-
able proto ns.
Base H
1
H
22
/H

NOE distance restraints (per strand)
Non-exchangeable NOE restraints 140
Exchangeable NOE restraints 22
Total restraints 162
Intra-residue 115
Inter-residue 47
Sugar dihedral restraints (per strand) 40
Hydrogen bond restraints 36
BFI (model obtained when iso BDNA is used as the starting duplex)
Number of convergent structures 39
rmsd from the average structure 0.5 A
˚
)1.0 A
˚
NOE violation > 0.2 A
˚
1
Dihedral angle violation > 5° Nil
BFII (modelobtained when iso BDNA is used as the starting duplex)
Number of convergent structures 20
rmsd from the average structure 0.3 A
˚
)1.0 A
˚
NOE violation > 0.2 A
˚
1
Dihedral angle violation > 5° Nil
AFI (model obtained when ADNA is used as the starting duplex)
Number of convergent structures 85

4
) duplex with the ideal iso BDNA (Fig. 7), demon-
strates a strong resemblance in the stacking patterns.
An estimate of the dimensions of major and minor
grooves is obtained by generating a 12mer duplex using t he
central hexamer of the average structure (AFI) as the repeat
using the program
FREEHELIX
[31]. The groove topologies of
AFI show significantly different features f rom the ideal
duplex models. T he major groove is wide (17 A
˚
), while its
minor groove is narrow (10.3 A
˚
).
The 3¢ deoxy sugars i n iso d(G
4
C
4
) favor N-type pucker,
corresponding to the C4¢ exo conformational domain ( P ¼
38–64°), except in the residue C7, which favors C4 ¢ exo/O4¢
endo pucker, corresponding to P ¼ 54–90° (Table 1) in
AFI. In any case, none of the sugars shows a tendency for
S-type sugar conformation.
Base pairs in A FI are slightly overwound, an d the duplex
has 9 bp per t urn, with an average helical twist o f 38.4° and
a rise of 3.76 A
˚

4
C
4
). (A) AFI an d
(B) BFI.
Fig. 4. Stereo plot of th e families of conv erged structures of is o
d(GGGGCCCC)
2
. (A) B FI (39 structures), (B) BFII (20 structures),
(C) AFI (85 structures), a nd (D) AFII ( 15 structures).
Table 5. Base-step parameters i n the average structure (AFI) of the iso
d(GGGGCCCC) duplex.
Base step Slide (A
˚
) X-disp (A
˚
) Twist (°) Rise (A
˚
)
G2-G3 )1.53 )3.36 42.3 3.68
G3-G4 )1.71 )3.13 39.67 3.61
G4-C5 )3.32 )3.19 28.02 4.23
C5-C6 )1.71 )3.13 39.63 3.61
C6-C7 )1.53 )3.23 42.37 3.68
Average )1.96 )3.20 38.39 3.76
Ó FEBS 2004 2¢,5¢ DNA with hybrid features of A and BDNA
1
(Eur. J. Biochem. 271) 2961
NMR structure of a 2¢,5¢ RNAfragment[11]thatexhibited
interesting features which supported our predictions from

()1.7 A
˚
). Thus, the base stacking pattern in iso d(G
4
C
4
)is
like that in ADNA, except at the GC step where a large
slide causes adjacent b ases to move aw ay, resu lting in
minimal overlap between them.
Another unusual feature is the predominance of N-type
pucker i n nearly all the 3 ¢ deoxy s ugars in 2¢,5¢ d(G
4
C
4
).
This is in sharp contrast to the S -type puckers preferred
by 2¢ deoxy sugars in DNA duplexes. This has been
Fig. 6. Base stacking at different steps in the AFI dup lex of is o (G
4
C
4
) and the GG steps of is o BDNA: iso ADNA and ADN A . Note the identic al base
stacking at the GG s teps of AFI a nd ideal duplex es. Figures were d rawn using 3
DNA
v1.5 [ 47].
2962 B. J. Premraj et al. (Eur. J. Biochem. 271) Ó FEBS 2004
anticipated in view of certain stereochemical arguments
[8,9]. Exclusive preference for the N-type sugar puckers
has, in fact, been indicated by the early NMR studies on

structure of iso d(G
4
C
4
) as a hybrid structure of A and B
forms.
It is grati fying that the more populated AFI family of iso
d(G
4
C
4
) resembles the ideal iso BDNA-like duplex [9],
which is also characterized by similar values of slide,
intermediate displacement, base stacking p attern and
extended nucleotide repeat formed out of N-type sugar
puckers (Table 5). Furthermore, the overall groove topol-
ogies of iso d(G
4
C
4
) resemble BDNA, with the widths of the
major groove and the minor groove having values of 17 A
˚
and 10.3 A
˚
, respectively (Table 8 ).
It has been demonstrated from modeling investigations
that 2¢,5¢ isomers, even with 3¢ deoxyriboses, cannot form
duplexes without base pair displacements [9]. Results of CD
and FTIR investigations on iso DNA fragments comprising

C7–G10 )22.4
Average )14.3
Table 7. Conformation angles (°) in the av erage structure (AFI) of th e iso d(GGGGCCCC)
2
duplex.
Residue
a
(P-O5¢)
b
(O5¢-C5)
c
(C4¢-C5¢)
n
(C2¢-O2¢)
f
(P-O2¢)
v
(C1¢-N) P
G1 – – 29 )115 )86 86.2 49
G2 )50 167 46 )78 )122 )137 37.6
G3 )31 138 36 )69 )131 )137 56.4
G4 )45 143 32 )87 )89 )142 49.5
C5 )68 )177 27 )76 )161 )138 62.7
C6 )25 128 35 )60 )133 )151 37.4
C7 )28 131 34 )90 )144 )140 70.7
C8 )44 158 39 – – )151 34.1
Ó FEBS 2004 2¢,5¢ DNA with hybrid features of A and BDNA
1
(Eur. J. Biochem. 271) 2963
2¢,5¢ nucleic acids causes t he base pairs t o s lide, resulting i n

duplex (AFI) with the ideal A and B types of duplexes formed by 3¢,5¢ and 2¢,5¢
links.
Features/parameters BDNA ADNA iso BDNA iso ADNA AFI
X-disp (A
˚
) )0.1 )4.7 )2.5 )4.7 )3.2
Slide (A
˚
) 0.4 )1.6 )1.7 )1.67 )1.96
Twist (°) 36 32.7 36 32.7 38.4
Rise (A
˚
) 3.4 2.56 3.4 2.56 3.76
No: res./turn 10 11 10 11  9.4
Inclination (°) 3.4 20.0 0 19.3 3
P–P separation (A
˚
) 7 5.9 7.5 5.9 7.4
Sugar pucker S type N type N type S type N type
C2¢endo C3¢endo C3¢endo C2¢endo C4¢exo
Major groove (A
˚
) 17 8.2 19.8 10.7 17
Minor groove (A
˚
) 11.7 16.9 10.5 14.8 10.3
2964 B. J. Premraj et al. (Eur. J. Biochem. 271) Ó FEBS 2004
which are mentioned above, probably impose additional
constraints limiting these capabilities. Also, it has been
shown f rom modeling c onsideration t hat the lateral slide

suggestthateven2¢,5¢ DNAs are pr one t o s equence e ffects,
as evidenced by some differences seen in structures of the
two sequences. The former sequence a ssumes a hybrid
structure of A and BDNA duplexes, while the latter assumes
an ADNA-like duplex with mixed C 2¢ endo and C3¢ endo
sugar puckers for t he central hexamer. The fact that both
these sequences, s tudied by NMR, point to a non-BDNA
duplex structure, suggest a constrained nature o f base p air
movements i n 2 ¢,5¢ nucleic acids vis-a
`
-vis their 3¢,5¢ isomers.
This is in complete conformity with the modeling studies
[8,9] which indicate that slide and X-displaceme nt of base
pairs lower than )1.7 A
˚
and )2.5 A
˚
, respectively, are
inaccessible owing to the inherent chemistry o f the 2 ¢,5¢-
linked sugar-phosphate backbone. It seems, then, that a
need for greater topological flexibility of DNA helices might
have had a bearing on the selection of 3¢,5¢ links over 2¢,5¢
links during the course of evolution.
Acknowledgements
NMR a nd c omputational facilities, provided by the National F acility
for High R esolution NMR at the Tata Institute of Fundamental
Research, Mumbai, are gratefully a cknowledged. N.Y. a nd B.J.P.
thank DST and CSIR f or a research g rant and senior f ellowship,
respectively. S.R. thank s CSIR for a Senior Research Fellowship. UGC
and DST are thanked for the financial support to the Department

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