Cyclic lipoundecapeptide tensin from Pseudomonas fluorescens strain 96.578

The crystal structure of the non-ribosomal lipoundecapeptide tensin from Pseudomonas fluorescens has been solved as an ethyl acetate/bis-water solvate (tensin ethyl acetate dihydrate, C₆₇H₁₁₅N₁₂O₂₀·C₄H₈O₂·2H₂O) to a resolution of 0.8 Å. The primary structure of tensin is β-hydroxydecanoyl-D-Leu-D-Asp-D-allo-Thr-D-Leu-D-Leu-D-Ser-L-Leu-D-Gln-L-Leu-L-Ile-L-Glu. The peptide is a lactone linking the Thr3 O_γ atom to the C-terminal C atom. The stereochemistry of the β-hydroxy acid has been shown to be S. The peptide shows structural resemblance to the non-ribosomal cyclic lipopeptide fengycin from Bacillus subtilis. The structure of tensin is essentially helical (3₁₀-helix), with the cyclic peptide wrapping around a hydrogen-bonded water molecule. The lipopeptide is amphipathic in good agreement with its function as a biosurfactant.

S1. Comment

Several bacterial genera characteristically produce a wide variety of extracellular low molecular weight compounds classified as siderophores, antibiotics and toxins. Some of these are peptides produced non-ribosomally by large multifunctional peptide synthethases (Marahiel, 1992). The component amino acids and lipids are activated in the form of adenylate, acylphosphorylate or coenzyme A derivatives before enzymatic condensation (Stachelhaus et al., 1998). It is now accepted, that this non-ribosomal synthetic route utilizing L–, D– and modified amino acids, is an alternative way of producing specialized peptides.

Bacillus subtilis has been a source of these bioactive peptides, especially the cyclic lipopeptides surfactin (Arima et al., 1968) with many isoforms, fengycin (Vanittanakom et al., 1986), and the members of the iturin family - iturin, mycosubtilin and bacillomycin (Peypoux et al., 1980). The plipstatins, which are very similar to fengycin have been isolates and characterized from Bacillus cereus (Umezawa et al., 1986). All of these compounds represent amphiphilic, membrane active biosurfactants with specific antimicrobial activities, and fengycin and the plipstatins inhibit phospholipase A2 (Umezawa et al., 1986).

Pseudomonas flourescens strains produce a number of cyclic lipopeptides with biosurfactant and antifungal properties, e.g. viscosinamide (Nielsen, Christophersen et al., 1999) and tensin (Nielsen, Thrane et al., 1999). In this paper we present the structure of tensin, (I), which is related to surfactin, a cyclic lipopeptide with seven amino acids in the lactone ring and with the hydroxy-oxygen of the β-hydroxy fatty acid involved in the lactone formation. The three-dimensional structure of surfactin has been established by NMR-spectroscopy (Bonmatin et al., 1994). Tensin is even more closely related to the cyclic lipopeptide fengycin with ten amino acids and to the white-line-inducing principle from Pseudomonas reactans with eight amino acids, and known crystal structure (Han et al., 1992). Many studies have been undertaken addressing the interaction of biosurfactants and membranes or lipid layer model systems. Surfactin has been used for many of these investigations (Sheppard et al., 1991; Grau et al., 1999). The general model of interaction between membranes and surfactin (and anionic biosurfactants in general) is pore formation by clustered peptides. In surfactin two closely situated carboxylic groups on the hydrophilic side also bind metal ions at high pH. The degree of surface penetration is still a subject of debate, but it appears as if the biosurfactants does not penetrate deeply into the membranes. Direct microscopic observations of the antagonistic activity against the plant pathogenic micro fungus Rhizoctonia solani suggested that tensin may affect the fungi differently as compared to viscosinamide studied previously (Nielsen, Thrane et al., 1999), which have Ca²⁺ channel forming properties (Thrane et al., 1999).

The structure of tensin is shown in figure 1. The absolute configuration fixed by the side-chain stereochemistry of isoleucine and threonine was supported by a Martley analysis (Martley, 1984). The Flack parameter was inconclusive. The peptide shows a disordered lipid and two disordered side-chains. This degree of disorder is comparable to what is seen in high-resolution protein structures. The peptide is essentially helical (3₁₀-helix from Leu 1 to Leu 7), with the rest of the cyclic peptide wrapping around a water molecule. The coordination of the water is close to tetrahedral and it is donating two and accepting two peptide hydrogen bonds. Another water molecule and an ethylacetate moiety are also found in the crystal structure. It is obvious that the molecule has two very different sides: a hydrophobic and a hydrophilic, in agreement with its function as a biosurfactant. The two residues that are negatively charged at high pH are situated on the hydrophilic side of the molecule, but are quite distant from each other. The closest distance between atoms of the two residues is 9.364 (7) Å, much longer than the difference observed in surfactin. This makes it unlikely that tensin can form 1:1 complexes with Ca²⁺ as surfactin (Maget-Dana et al., 1992), at least in the conformation observed in this crystal structure. It is however common that these non-ribosomal lipopeptides can adopt a number of distinct and different conformations. This is for example the case for surfactin, where the NMR studies revealed two very different conformations (Bonmatin et al., 1994). The conformation of surfactin has also been shown to be highly dependent on the nature of the solvent (Itokawa et al., 1994). Inspection of the structure seems to suggest that major degrees of freedom of the tensin molecule are associated with the ϕ and ψ angles of Asp 2 and the ϕ value of Thr 3. The conformation of the rest of the molecule appears to be fixed by the lactone-ring formation. Changes of one of these three angles will make it possible to position the lipid chain orthogonal to the plane of the tensin ring. This in turn would make tensin an analogue of a phospholipid with a very bulky head group. If the rings now associate (e.g. via complexation of metal ions by the carboxylate groups from adjacent tensins) this could be the structural basis of the pore formation in biological membranes.

The packing in the crystal does not suggest multimerization of the tensin molecules, and the hydrophobic tail of the lipid is seen to pack closely to the rest of the peptide. Hence, in order to obtain information on more biologically relevant conformations, structural and functional studies of the molecule when absorbed into living membranes should be undertaken.

S2. Experimental

Tensin was isolated and purified as desribed elsewhere (Nielsen, Thrane et al., 1999). The crystals were grown from a water-saturated ethyl acetate solution at 278 K. Crystals suitable for single-crystal X-ray diffraction appeared after one month.

S3. Refinement

All ordered and major conformation (~70% occupancy) non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were located in difference fourier maps and treated as riding to the appropiate heavy atoms. A number of the residues were found to have more than one conformation. The last seven carbon atoms of the lipid group were found to occupy two positions. Also all atoms after C_α of L5 and all atoms after C_α of E12 showed two different conformations. This relatively high degree of disorder is probably the reason for the R-factor and internal R-factor being somewhat high compared to average small molecule data.

Computing details

Data collection: CAD-4 Express (Enraf-Nonius, 1994); cell refinement: CAD-4 Express; data reduction: XCAD4 (Harms, 1996); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: VMD (Humphrey et al., 1996); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. Stereo VMD (Humphrey et al., 1996) drawing of the title compound. Only the most occupied sites of the lipid, Leu 5 and Glu 11 are drawn. The lipid is in the N/terminal end, while the C-terminal end forms a lactone with Thr 3. The molecule is viewed from its polar side with the hydrogen-bonded water molecule included.

S-β-hydroxydecanoyl-D-Leu-D-Asp-D-allo-Thr-D-Leu-D-Leu-D-Ser-L-Leu- D-Gln-L-Leu-L-Ile-L-Glu:ethylacetate:dihydrate

Crystal data

C67H115N12O20·C4H8O2·2H2O	Dx = 1.138 Mg m^−3
Mr = 1532.84	Cu Kα radiation, λ = 1.54180 Å
Orthorhombic, P212121	Cell parameters from 20 reflections
a = 13.245 (10) Å	θ = 40.3–43.6°
b = 21.984 (10) Å	µ = 0.71 mm^−1
c = 30.732 (10) Å	T = 122 K
V = 8948 (8) Å^3	Prism, colourless
Z = 4	0.32 × 0.23 × 0.15 mm
F(000) = 3316

Data collection

Enraf Nonius CAD4 diffractometer	Rint = 0.087
Radiation source: fine-focus sealed tube	θmax = 75.0°, θmin = 2.5°
Graphite monochromator	h = −16→16
ω–2θ scans	k = 0→27
21476 measured reflections	l = −37→38
11858 independent reflections	5 standard reflections every 166.7 min
8739 reflections with I > 2σ(I)	intensity decay: 5.6%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.070	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.205	w = 1/[σ^2(Fo^2) + (0.1131P)^2 + 1.4802P] where P = (Fo^2 + 2Fc^2)/3
S = 1.04	(Δ/σ)max = 0.025
11858 reflections	Δρmax = 0.41 e Å^−3
1031 parameters	Δρmin = −0.40 e Å^−3
34 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.3 (3)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)

are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based

on F, with F set to zero for negative F². The threshold expression of

F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

The structure was solved by direct methods and refined with the full-matrix least-squares technique.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
C3	0.1179 (7)	0.8020 (4)	0.1832 (3)	0.045 (2)	0.723 (7)
H3A	0.0636	0.7792	0.1697	0.054*	0.723 (7)
H3B	0.0914	0.8415	0.1915	0.054*	0.723 (7)
C4	0.1530 (8)	0.7686 (5)	0.2238 (3)	0.059 (2)*	0.723 (7)
H4A	0.1733	0.7277	0.2158	0.071*	0.723 (7)
H4B	0.2118	0.7892	0.2355	0.071*	0.723 (7)
C5	0.0747 (7)	0.7649 (4)	0.2583 (3)	0.052 (2)*	0.723 (7)
H5A	0.0187	0.7406	0.2477	0.063*	0.723 (7)
H5B	0.0494	0.8054	0.2643	0.063*	0.723 (7)
C6	0.1146 (11)	0.7370 (6)	0.3003 (4)	0.068 (3)*	0.723 (7)
H6A	0.1718	0.7609	0.3101	0.081*	0.723 (7)
H6B	0.1391	0.6964	0.2939	0.081*	0.723 (7)
C7	0.0387 (7)	0.7327 (4)	0.3376 (3)	0.055 (2)	0.723 (7)
H7A	0.0090	0.7726	0.3418	0.066*	0.723 (7)
H7B	−0.0151	0.7054	0.3288	0.066*	0.723 (7)
C8	0.0793 (9)	0.7112 (6)	0.3803 (4)	0.086 (4)	0.723 (7)
H8A	0.1028	0.6697	0.3768	0.103*	0.723 (7)
H8B	0.1374	0.7359	0.3877	0.103*	0.723 (7)
C9	0.0078 (10)	0.7129 (5)	0.4171 (4)	0.079 (3)	0.723 (7)
H9A	0.0404	0.6976	0.4428	0.118*	0.723 (7)
H9B	−0.0499	0.6881	0.4105	0.118*	0.723 (7)
H9C	−0.0136	0.7540	0.4220	0.118*	0.723 (7)
C3'	0.0918 (16)	0.7944 (9)	0.1681 (6)	0.028 (5)*	0.277 (7)
H3C	0.0575	0.8319	0.1758	0.033*	0.277 (7)
H3D	0.0540	0.7757	0.1446	0.033*	0.277 (7)
C4'	0.0891 (17)	0.7514 (9)	0.2078 (6)	0.044 (5)*	0.277 (7)
H4C	0.1212	0.7133	0.2001	0.053*	0.277 (7)
H4D	0.0194	0.7429	0.2153	0.053*	0.277 (7)
C5'	0.147 (2)	0.7809 (11)	0.2506 (8)	0.056 (6)*	0.277 (7)
H5C	0.2170	0.7897	0.2437	0.067*	0.277 (7)
H5D	0.1143	0.8183	0.2594	0.067*	0.277 (7)
C6'	0.141 (3)	0.7322 (17)	0.2882 (12)	0.077 (10)*	0.277 (7)
H6C	0.1390	0.7543	0.3155	0.092*	0.277 (7)
H6D	0.0760	0.7118	0.2854	0.092*	0.277 (7)
C7'	0.214 (2)	0.6876 (12)	0.2921 (8)	0.062 (6)*	0.277 (7)
H7C	0.2789	0.7069	0.2885	0.074*	0.277 (7)
H7D	0.2051	0.6596	0.2679	0.074*	0.277 (7)
C8'	0.218 (3)	0.6485 (15)	0.3356 (11)	0.088 (9)*	0.277 (7)
H8C	0.2378	0.6747	0.3594	0.105*	0.277 (7)
H8D	0.1503	0.6335	0.3419	0.105*	0.277 (7)
C9'	0.289 (4)	0.595 (2)	0.3333 (14)	0.122 (15)*	0.277 (7)
H9D	0.2870	0.5728	0.3602	0.184*	0.277 (7)
H9E	0.3568	0.6095	0.3285	0.184*	0.277 (7)
H9F	0.2699	0.5687	0.3098	0.184*	0.277 (7)
O	0.1788 (3)	0.93968 (14)	0.15981 (10)	0.0327 (7)
C	0.1578 (4)	0.9172 (2)	0.12374 (15)	0.0338 (10)
C1	0.1807 (6)	0.8513 (2)	0.11253 (18)	0.0468 (14)
H1A	0.1241	0.8349	0.0963	0.056*
H1B	0.2393	0.8503	0.0936	0.056*
C2	0.2004 (4)	0.8107 (2)	0.15093 (17)	0.0373 (11)
H2	0.2562	0.8296	0.1669	0.045*
O1	0.2386 (3)	0.75343 (16)	0.13533 (14)	0.0488 (10)
N_1	0.1186 (3)	0.95061 (18)	0.09162 (12)	0.0319 (8)
H0_1	0.1068	0.9341	0.0667	0.038*
CA_1	0.0954 (4)	1.0154 (2)	0.09842 (15)	0.0324 (10)
HA_1	0.0424	1.0186	0.1206	0.039*
C_1	0.1866 (4)	1.0499 (2)	0.11389 (14)	0.0311 (10)
O_1	0.1771 (3)	1.09158 (15)	0.14098 (10)	0.0370 (8)
CB_1	0.0561 (4)	1.0436 (3)	0.05569 (17)	0.0414 (12)
HB1_1	0.0510	1.0873	0.0597	0.050*
HB2_1	0.1058	1.0364	0.0331	0.050*
CG_1	−0.0464 (6)	1.0200 (3)	0.0396 (2)	0.0575 (17)
HG_1	−0.0391	0.9765	0.0333	0.069*
CD1_1	−0.0734 (7)	1.0522 (3)	−0.0032 (3)	0.078 (3)
HD1A_1	−0.0191	1.0473	−0.0236	0.118*
HD1B_1	−0.0840	1.0947	0.0022	0.118*
HD1C_1	−0.1339	1.0347	−0.0150	0.118*
CD2_1	−0.1320 (5)	1.0272 (4)	0.0726 (3)	0.076 (2)
HD2A_1	−0.1136	1.0074	0.0993	0.113*
HD2B_1	−0.1924	1.0090	0.0613	0.113*
HD2C_1	−0.1436	1.0696	0.0780	0.113*
N_2	0.2760 (3)	1.03586 (16)	0.09652 (11)	0.0290 (8)
H0_2	0.2796	1.0071	0.0776	0.035*
CA_2	0.3669 (4)	1.0681 (2)	0.10879 (15)	0.0323 (10)
HA_2	0.3517	1.1116	0.1063	0.039*
C_2	0.3972 (4)	1.0567 (2)	0.15619 (14)	0.0357 (11)
O_2	0.4504 (4)	1.0938 (2)	0.17522 (12)	0.0612 (13)
CB_2	0.4538 (4)	1.0554 (2)	0.07804 (15)	0.0336 (10)
HB1_2	0.4359	1.0707	0.0494	0.040*
HB2_2	0.5122	1.0782	0.0879	0.040*
CG_2	0.4834 (4)	0.9894 (2)	0.07372 (15)	0.0334 (10)
OD1_2	0.5623 (3)	0.9842 (2)	0.04751 (14)	0.0460 (10)
OD2_2	0.4412 (3)	0.94763 (15)	0.09161 (11)	0.0380 (8)
HD1_2	0.569 (7)	0.948 (4)	0.042 (3)	0.04 (3)*
N_3	0.3634 (3)	1.00631 (16)	0.17544 (11)	0.0278 (8)
H0_3	0.3311	0.9796	0.1605	0.033*
CA_3	0.3809 (4)	0.99638 (19)	0.22142 (14)	0.0285 (9)
HA_3	0.4498	1.0098	0.2281	0.034*
C_3	0.3078 (4)	1.03506 (19)	0.24844 (14)	0.0281 (9)
O_3	0.3387 (3)	1.06449 (14)	0.28036 (10)	0.0307 (7)
CB_3	0.3740 (5)	0.9281 (2)	0.23162 (15)	0.0370 (11)
HB_3	0.3056	0.9130	0.2262	0.044*
OG1_3	0.3994 (3)	0.92265 (15)	0.27750 (10)	0.0378 (8)
CG2_3	0.4497 (6)	0.8920 (3)	0.20660 (18)	0.0604 (19)
HG2A_3	0.4426	0.8497	0.2137	0.091*
HG2B_3	0.5165	0.9054	0.2140	0.091*
HG2C_3	0.4386	0.8976	0.1760	0.091*
N_4	0.2122 (3)	1.03785 (17)	0.23571 (12)	0.0298 (8)
H0_4	0.1910	1.0157	0.2145	0.036*
CA_4	0.1433 (4)	1.0795 (2)	0.25843 (15)	0.0312 (10)
HA_4	0.1388	1.0665	0.2889	0.037*
C_4	0.1842 (4)	1.1445 (2)	0.25742 (14)	0.0305 (10)
O_4	0.1803 (3)	1.17747 (15)	0.29038 (10)	0.0387 (8)
CB_4	0.0377 (4)	1.0770 (3)	0.23882 (19)	0.0437 (12)
HB1_4	−0.0037	1.1075	0.2530	0.052*
HB2_4	0.0423	1.0879	0.2083	0.052*
CG_4	−0.0147 (7)	1.0165 (4)	0.2424 (3)	0.081 (2)
HG_4	0.0195	0.9910	0.2209	0.097*
CD1_4	−0.1234 (7)	1.0245 (6)	0.2236 (4)	0.120 (4)
HD1A_4	−0.1204	1.0486	0.1976	0.181*
HD1B_4	−0.1652	1.0446	0.2447	0.181*
HD1C_4	−0.1515	0.9854	0.2170	0.181*
CD2_4	−0.0072 (10)	0.9840 (6)	0.2801 (5)	0.168 (7)
HD2A_4	−0.0438	0.9465	0.2772	0.252*
HD2B_4	−0.0352	1.0072	0.3037	0.252*
HD2C_4	0.0625	0.9754	0.2860	0.252*
CB_5	0.2534 (12)	1.2436 (5)	0.1641 (4)	0.028 (3)	0.681 (9)
HB1_5	0.3020	1.2184	0.1488	0.033*	0.681 (9)
HB2_5	0.1869	1.2339	0.1528	0.033*	0.681 (9)
CG_5	0.2769 (7)	1.3120 (3)	0.1544 (2)	0.0337 (18)	0.681 (9)
HG_5	0.3475	1.3198	0.1621	0.040*	0.681 (9)
CD1_5	0.2654 (8)	1.3206 (4)	0.1049 (2)	0.045 (2)	0.681 (9)
HD1A_5	0.3084	1.2923	0.0900	0.067*	0.681 (9)
HD1B_5	0.2842	1.3614	0.0972	0.067*	0.681 (9)
HD1C_5	0.1965	1.3135	0.0967	0.067*	0.681 (9)
CD2_5	0.2116 (8)	1.3562 (3)	0.1793 (3)	0.052 (2)	0.681 (9)
HD2A_5	0.2225	1.3510	0.2099	0.078*	0.681 (9)
HD2B_5	0.1419	1.3487	0.1726	0.078*	0.681 (9)
HD2C_5	0.2288	1.3970	0.1711	0.078*	0.681 (9)
CB_5'	0.244 (4)	1.244 (2)	0.1717 (13)	0.063 (17)*	0.319 (9)
HB3_5	0.2804	1.2145	0.1539	0.076*	0.319 (9)
HB4_5	0.2771	1.2828	0.1676	0.076*	0.319 (9)
CG_5'	0.134 (3)	1.2492 (15)	0.1529 (10)	0.090 (9)*	0.319 (9)
HG1_5	0.0962	1.2129	0.1613	0.108*	0.319 (9)
CD1_5'	0.087 (3)	1.3098 (19)	0.1799 (13)	0.134 (14)*	0.319 (9)
HD1D_5	0.0855	1.3012	0.2105	0.201*	0.319 (9)
HD1E_5	0.0195	1.3178	0.1699	0.201*	0.319 (9)
HD1F_5	0.1286	1.3447	0.1747	0.201*	0.319 (9)
CD2_5'	0.120 (5)	1.260 (3)	0.1094 (17)	0.20 (2)*	0.319 (9)
HD2D_5	0.1545	1.2290	0.0928	0.298*	0.319 (9)
HD2E_5	0.1463	1.2990	0.1019	0.298*	0.319 (9)
HD2F_5	0.0491	1.2583	0.1029	0.298*	0.319 (9)
N_5	0.2203 (3)	1.16454 (17)	0.21948 (12)	0.0324 (9)
H0_5	0.2224	1.1401	0.1976	0.039*
CA_5	0.2567 (4)	1.2273 (2)	0.21401 (14)	0.0339 (11)
HA_5	0.2092	1.2543	0.2290	0.041*
C_5	0.3608 (5)	1.2387 (2)	0.23284 (15)	0.0396 (12)
O_5	0.3965 (4)	1.29016 (18)	0.23369 (14)	0.0591 (13)
N_6	0.4093 (3)	1.19088 (18)	0.25092 (12)	0.0341 (9)
H0_6	0.3822	1.1554	0.2501	0.041*
CA_6	0.5071 (4)	1.1990 (2)	0.27177 (15)	0.0376 (11)
HA_6	0.5516	1.2208	0.2517	0.045*
C_6	0.4983 (4)	1.2358 (2)	0.31367 (15)	0.0315 (10)
O_6	0.5748 (3)	1.25535 (17)	0.33150 (12)	0.0416 (9)
CB_6	0.5551 (5)	1.1393 (3)	0.28285 (19)	0.0461 (13)
HB1_6	0.5524	1.1129	0.2575	0.055*
HB2_6	0.6256	1.1460	0.2899	0.055*
OG_6	0.5077 (3)	1.10927 (16)	0.31849 (11)	0.0405 (8)
HG_6	0.4483	1.1028	0.3126	0.061*
N_7	0.4066 (3)	1.24178 (17)	0.33158 (11)	0.0285 (8)
H0_7	0.3557	1.2252	0.3190	0.034*
CA_7	0.3907 (4)	1.27548 (19)	0.37170 (14)	0.0277 (9)
HA_7	0.4341	1.3115	0.3708	0.033*
C_7	0.4194 (3)	1.2389 (2)	0.41228 (14)	0.0266 (9)
O_7	0.4144 (3)	1.26287 (15)	0.44844 (10)	0.0337 (7)
CB_7	0.2809 (4)	1.2976 (2)	0.37321 (17)	0.0342 (10)
HB1_7	0.2365	1.2636	0.3671	0.041*
HB2_7	0.2659	1.3119	0.4024	0.041*
CG_7	0.2592 (5)	1.3485 (3)	0.3409 (2)	0.0494 (14)
HG_7	0.2912	1.3387	0.3131	0.059*
CD1_7	0.1435 (6)	1.3528 (4)	0.3342 (4)	0.100 (3)
HD1A_7	0.1184	1.3144	0.3240	0.150*
HD1B_7	0.1287	1.3838	0.3132	0.150*
HD1C_7	0.1116	1.3627	0.3614	0.150*
CD2_7	0.3004 (6)	1.4082 (3)	0.3571 (2)	0.0593 (17)
HD2A_7	0.2864	1.4395	0.3362	0.089*
HD2B_7	0.3720	1.4048	0.3612	0.089*
HD2C_7	0.2689	1.4183	0.3843	0.089*
N_8	0.4500 (3)	1.18165 (16)	0.40652 (11)	0.0257 (7)
H0_8	0.4488	1.1660	0.3809	0.031*
CA_8	0.4855 (3)	1.1452 (2)	0.44301 (14)	0.0270 (9)
HA_8	0.5338	1.1697	0.4596	0.032*
C_8	0.4009 (4)	1.12603 (19)	0.47374 (13)	0.0254 (9)
O_8	0.4215 (3)	1.11024 (16)	0.51113 (10)	0.0355 (8)
CB_8	0.5411 (4)	1.0893 (2)	0.42575 (15)	0.0314 (10)
HB1_8	0.4987	1.0689	0.4045	0.038*
HB2_8	0.5530	1.0613	0.4496	0.038*
CG_8	0.6423 (4)	1.1056 (2)	0.40452 (16)	0.0350 (10)
HG1_8	0.6631	1.0724	0.3857	0.042*
HG2_8	0.6334	1.1414	0.3865	0.042*
CD_8	0.7249 (4)	1.1178 (2)	0.43772 (15)	0.0327 (10)
OE1_8	0.7224 (3)	1.09298 (16)	0.47376 (12)	0.0415 (8)
NE2_8	0.8010 (3)	1.1529 (2)	0.42516 (15)	0.0426 (10)
HE2A_8	0.8511	1.1591	0.4424	0.051*
HE2B_8	0.8002	1.1694	0.3998	0.051*
N_9	0.3071 (3)	1.12688 (16)	0.45799 (11)	0.0248 (7)
H0_9	0.2980	1.1390	0.4317	0.030*
CA_9	0.2191 (4)	1.1082 (2)	0.48334 (13)	0.0265 (9)
HA_9	0.2327	1.1164	0.5141	0.032*
C_9	0.2017 (3)	1.04007 (19)	0.47778 (13)	0.0254 (9)
O_9	0.1979 (3)	1.00418 (15)	0.50891 (10)	0.0366 (8)
CB_9	0.1254 (4)	1.1444 (2)	0.46968 (15)	0.0305 (10)
HB1_9	0.0713	1.1358	0.4900	0.037*
HB2_9	0.1039	1.1305	0.4412	0.037*
CG_9	0.1417 (4)	1.2136 (2)	0.46785 (16)	0.0340 (10)
HG_9	0.1935	1.2215	0.4458	0.041*
CD1_9	0.1795 (4)	1.2392 (2)	0.51022 (19)	0.0441 (13)
HD1A_9	0.2405	1.2185	0.5185	0.066*
HD1B_9	0.1292	1.2335	0.5323	0.066*
HD1C_9	0.1930	1.2818	0.5069	0.066*
CD2_9	0.0459 (4)	1.2449 (2)	0.45312 (17)	0.0411 (12)
HD2A_9	0.0243	1.2278	0.4259	0.062*
HD2B_9	0.0585	1.2876	0.4495	0.062*
HD2C_9	−0.0058	1.2392	0.4746	0.062*
N_10	0.1910 (4)	1.02259 (17)	0.43632 (12)	0.0335 (9)
H0_10	0.1917	1.0508	0.4169	0.040*
CA_10	0.1787 (4)	0.9617 (2)	0.42122 (15)	0.0343 (10)
HA_10	0.1904	0.9333	0.4452	0.041*
C_10	0.2570 (5)	0.9519 (2)	0.38630 (16)	0.0394 (12)
O_10	0.2770 (4)	0.99305 (17)	0.36062 (14)	0.0663 (15)
CB_10	0.0700 (5)	0.9528 (3)	0.4031 (2)	0.0542 (15)
HB_10	0.0605	0.9828	0.3799	0.065*
CG1_10	−0.0085 (5)	0.9677 (4)	0.4394 (3)	0.070 (2)
HG1A_10	−0.0098	0.9343	0.4601	0.083*
HG1B_10	0.0135	1.0038	0.4548	0.083*
CG2_10	0.0520 (7)	0.8922 (3)	0.3839 (3)	0.075 (2)
HG2A_10	−0.0161	0.8900	0.3733	0.112*
HG2B_10	0.0622	0.8615	0.4056	0.112*
HG2C_10	0.0981	0.8858	0.3602	0.112*
CD1_10	−0.1168 (6)	0.9783 (4)	0.4223 (4)	0.091 (3)
HD1A_10	−0.1608	0.9874	0.4462	0.137*
HD1B_10	−0.1401	0.9423	0.4077	0.137*
HD1C_10	−0.1167	1.0118	0.4022	0.137*
N_11	0.3010 (4)	0.89743 (18)	0.38294 (13)	0.0426 (11)
H0_11	0.2864	0.8688	0.4009	0.051*
CA_11	0.3744 (5)	0.8875 (2)	0.34815 (16)	0.0467 (14)
HA_11	0.4359	0.9113	0.3529	0.056*
C_11	0.3280 (5)	0.9013 (2)	0.30415 (16)	0.0436 (13)
O_11	0.2413 (4)	0.8913 (3)	0.29452 (15)	0.0749 (15)
CB_11	0.3990 (6)	0.8172 (3)	0.3434 (2)	0.0324 (17)	0.664 (9)
HB1_11	0.3368	0.7944	0.3399	0.039*	0.664 (9)
HB2_11	0.4405	0.8105	0.3178	0.039*	0.664 (9)
CG_11	0.4543 (7)	0.7957 (3)	0.3836 (2)	0.038 (2)	0.664 (9)
HG1_11	0.4096	0.7989	0.4085	0.046*	0.664 (9)
HG2_11	0.5117	0.8221	0.3888	0.046*	0.664 (9)
CD_11	0.4919 (9)	0.7294 (5)	0.3798 (3)	0.038 (3)	0.664 (9)
OE1_11	0.5314 (6)	0.7046 (3)	0.41120 (19)	0.0497 (18)	0.664 (9)
OE2_11	0.4807 (5)	0.7058 (3)	0.34168 (19)	0.0456 (17)*	0.664 (9)
HE2_11	0.5013	0.6707	0.3419	0.068*	0.664 (9)
CB_11'	0.4427 (11)	0.8338 (6)	0.3582 (5)	0.039 (4)*	0.336 (9)
HB3_11	0.5007	0.8340	0.3389	0.046*	0.336 (9)
HB4_11	0.4667	0.8361	0.3879	0.046*	0.336 (9)
CG_11'	0.3822 (13)	0.7772 (6)	0.3517 (6)	0.050 (5)*	0.336 (9)
HG3_11	0.3538	0.7778	0.3226	0.060*	0.336 (9)
HG4_11	0.3264	0.7774	0.3721	0.060*	0.336 (9)
CD_11'	0.4407 (12)	0.7189 (6)	0.3574 (5)	0.042 (4)*	0.336 (9)
OE1_11'	0.4164 (10)	0.6780 (5)	0.3318 (4)	0.051 (4)*	0.336 (9)
OE2_11'	0.5106 (16)	0.7173 (11)	0.3856 (8)	0.064 (7)*	0.336 (9)
HE2A_11	0.5426	0.6856	0.3829	0.096*	0.336 (9)
C_12	0.2493 (10)	0.7925 (4)	0.4874 (3)	0.100 (4)
C1_12	0.2223 (11)	0.8335 (4)	0.5246 (3)	0.119 (4)
H1A_12	0.2258	0.8111	0.5514	0.178*
H1B_12	0.1550	0.8488	0.5206	0.178*
H1C_12	0.2688	0.8670	0.5257	0.178*
O_12	0.2517 (7)	0.8072 (2)	0.44995 (18)	0.107 (3)
O1_12	0.2722 (7)	0.7370 (3)	0.50026 (19)	0.111 (3)
C2_12	0.3038 (10)	0.6923 (4)	0.4687 (3)	0.101 (4)
H2A_12	0.2486	0.6833	0.4490	0.121*
H2B_12	0.3598	0.7080	0.4517	0.121*
C3_12	0.3341 (8)	0.6382 (4)	0.4911 (3)	0.094 (3)
H3A_12	0.3553	0.6082	0.4703	0.140*
H3B_12	0.2782	0.6227	0.5076	0.140*
H3C_12	0.3891	0.6474	0.5104	0.140*
O1_13	0.2399 (3)	1.11851 (17)	0.36699 (10)	0.0366 (8)
H1_13	0.209 (5)	1.137 (3)	0.346 (2)	0.046 (17)*
H2_13	0.268 (5)	1.091 (3)	0.361 (2)	0.04 (2)*
O1_14	0.6164 (3)	0.8782 (2)	0.02202 (14)	0.0454 (9)
H1_14	0.607 (6)	0.915 (4)	0.033 (3)	0.18 (2)*
H2_14	0.614 (6)	0.845 (3)	0.033 (2)	0.07 (2)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C3	0.039 (5)	0.033 (4)	0.064 (6)	0.007 (3)	−0.010 (4)	0.000 (4)
C7	0.060 (5)	0.045 (4)	0.060 (5)	0.001 (4)	0.000 (4)	−0.006 (4)
C8	0.065 (7)	0.093 (8)	0.101 (9)	0.013 (6)	0.016 (7)	0.055 (7)
C9	0.090 (8)	0.063 (6)	0.083 (7)	−0.008 (6)	0.009 (7)	0.019 (6)
O	0.0414 (19)	0.0326 (16)	0.0240 (15)	−0.0060 (15)	−0.0025 (14)	−0.0046 (12)
C	0.039 (3)	0.034 (2)	0.028 (2)	−0.005 (2)	0.002 (2)	−0.0070 (19)
C1	0.073 (4)	0.031 (2)	0.036 (3)	−0.003 (3)	−0.003 (3)	−0.009 (2)
C2	0.038 (3)	0.035 (2)	0.039 (3)	0.005 (2)	−0.011 (2)	−0.011 (2)
O1	0.048 (2)	0.0362 (18)	0.063 (2)	0.0086 (18)	−0.006 (2)	−0.0202 (18)
N_1	0.039 (2)	0.038 (2)	0.0189 (17)	−0.0013 (18)	−0.0024 (16)	−0.0103 (15)
CA_1	0.035 (2)	0.039 (2)	0.024 (2)	0.003 (2)	0.001 (2)	−0.0035 (19)
C_1	0.042 (3)	0.031 (2)	0.0208 (19)	0.002 (2)	−0.001 (2)	−0.0042 (17)
O_1	0.048 (2)	0.0371 (17)	0.0258 (16)	0.0053 (16)	−0.0007 (15)	−0.0117 (13)
CB_1	0.047 (3)	0.044 (3)	0.033 (3)	−0.001 (3)	−0.008 (2)	−0.006 (2)
CG_1	0.066 (4)	0.048 (3)	0.059 (4)	0.014 (3)	−0.023 (3)	−0.012 (3)
CD1_1	0.088 (6)	0.065 (4)	0.083 (5)	0.024 (4)	−0.049 (5)	−0.013 (4)
CD2_1	0.048 (4)	0.084 (5)	0.095 (6)	−0.003 (4)	−0.018 (4)	−0.007 (5)
N_2	0.042 (2)	0.0257 (17)	0.0196 (16)	−0.0043 (17)	0.0008 (17)	−0.0055 (14)
CA_2	0.044 (3)	0.023 (2)	0.029 (2)	−0.004 (2)	0.004 (2)	−0.0012 (17)
C_2	0.046 (3)	0.040 (2)	0.021 (2)	−0.014 (2)	0.005 (2)	−0.0050 (18)
O_2	0.089 (3)	0.069 (3)	0.0262 (18)	−0.053 (3)	−0.003 (2)	−0.0019 (18)
CB_2	0.046 (3)	0.033 (2)	0.022 (2)	−0.009 (2)	0.003 (2)	0.0013 (18)
CG_2	0.042 (3)	0.037 (2)	0.022 (2)	0.000 (2)	0.007 (2)	−0.0023 (18)
OD1_2	0.047 (2)	0.038 (2)	0.053 (2)	0.0033 (18)	0.0212 (19)	0.0004 (17)
OD2_2	0.051 (2)	0.0328 (16)	0.0303 (16)	−0.0005 (16)	0.0110 (16)	0.0011 (14)
N_3	0.038 (2)	0.0259 (17)	0.0190 (16)	−0.0034 (16)	0.0002 (16)	−0.0057 (14)
CA_3	0.037 (2)	0.028 (2)	0.020 (2)	−0.0001 (19)	0.0016 (19)	−0.0036 (16)
C_3	0.041 (3)	0.0240 (19)	0.0194 (19)	−0.0041 (19)	−0.0007 (19)	−0.0028 (16)
O_3	0.0417 (19)	0.0308 (16)	0.0197 (14)	0.0000 (14)	−0.0043 (14)	−0.0055 (12)
CB_3	0.055 (3)	0.029 (2)	0.027 (2)	0.009 (2)	−0.001 (2)	−0.0029 (18)
OG1_3	0.056 (2)	0.0349 (16)	0.0224 (15)	0.0074 (17)	0.0021 (16)	0.0045 (13)
CG2_3	0.095 (5)	0.052 (3)	0.034 (3)	0.037 (4)	0.008 (3)	−0.011 (2)
N_4	0.035 (2)	0.0303 (18)	0.0244 (17)	−0.0024 (17)	−0.0011 (16)	−0.0065 (15)
CA_4	0.032 (2)	0.037 (2)	0.024 (2)	0.002 (2)	0.0052 (19)	−0.0056 (18)
C_4	0.036 (2)	0.033 (2)	0.023 (2)	0.009 (2)	−0.0011 (19)	−0.0013 (17)
O_4	0.057 (2)	0.0341 (16)	0.0247 (16)	0.0096 (17)	0.0031 (16)	−0.0037 (13)
CB_4	0.033 (3)	0.058 (3)	0.040 (3)	0.000 (3)	0.002 (2)	−0.004 (3)
CG_4	0.066 (5)	0.082 (5)	0.095 (6)	−0.025 (4)	−0.016 (5)	0.006 (5)
CD1_4	0.068 (6)	0.130 (9)	0.163 (11)	−0.027 (6)	−0.030 (7)	−0.033 (8)
CD2_4	0.118 (10)	0.164 (12)	0.222 (16)	−0.097 (9)	−0.060 (10)	0.106 (12)
CB_5	0.049 (6)	0.025 (4)	0.009 (3)	0.009 (3)	−0.006 (3)	0.002 (3)
CG_5	0.053 (5)	0.028 (3)	0.020 (3)	0.007 (3)	0.000 (3)	0.005 (2)
CD1_5	0.065 (5)	0.046 (4)	0.024 (3)	0.006 (4)	−0.005 (4)	0.011 (3)
CD2_5	0.069 (6)	0.033 (4)	0.053 (5)	0.024 (4)	−0.010 (5)	−0.001 (3)
N_5	0.047 (2)	0.0281 (18)	0.0220 (17)	−0.0003 (18)	−0.0006 (18)	−0.0018 (14)
CA_5	0.055 (3)	0.027 (2)	0.020 (2)	0.000 (2)	−0.002 (2)	−0.0012 (16)
C_5	0.062 (3)	0.040 (3)	0.017 (2)	−0.007 (3)	−0.004 (2)	0.0041 (19)
O_5	0.085 (3)	0.040 (2)	0.052 (2)	−0.025 (2)	−0.027 (2)	0.0174 (18)
N_6	0.046 (2)	0.0336 (19)	0.0222 (18)	−0.0105 (19)	−0.0069 (18)	0.0030 (15)
CA_6	0.043 (3)	0.045 (3)	0.025 (2)	−0.015 (2)	0.001 (2)	−0.003 (2)
C_6	0.036 (3)	0.034 (2)	0.025 (2)	−0.012 (2)	−0.001 (2)	0.0045 (18)
O_6	0.0373 (19)	0.046 (2)	0.041 (2)	−0.0167 (17)	−0.0027 (16)	−0.0057 (16)
CB_6	0.045 (3)	0.052 (3)	0.041 (3)	−0.004 (3)	−0.001 (3)	−0.006 (2)
OG_6	0.045 (2)	0.0426 (19)	0.0336 (18)	−0.0065 (17)	−0.0093 (16)	−0.0002 (15)
N_7	0.034 (2)	0.0306 (18)	0.0213 (17)	−0.0123 (17)	−0.0050 (16)	−0.0002 (14)
CA_7	0.036 (2)	0.0228 (19)	0.024 (2)	−0.0059 (19)	−0.0060 (19)	0.0033 (16)
C_7	0.029 (2)	0.030 (2)	0.021 (2)	−0.0041 (19)	−0.0002 (17)	0.0037 (17)
O_7	0.0434 (19)	0.0350 (16)	0.0227 (15)	0.0061 (15)	−0.0031 (14)	−0.0029 (12)
CB_7	0.036 (3)	0.029 (2)	0.037 (2)	−0.002 (2)	−0.004 (2)	0.0074 (19)
CG_7	0.046 (3)	0.043 (3)	0.059 (4)	−0.002 (3)	−0.021 (3)	0.016 (3)
CD1_7	0.061 (5)	0.091 (6)	0.148 (9)	0.001 (5)	−0.055 (6)	0.044 (6)
CD2_7	0.064 (4)	0.038 (3)	0.076 (4)	0.004 (3)	−0.011 (4)	0.012 (3)
N_8	0.0304 (19)	0.0298 (17)	0.0168 (16)	−0.0012 (16)	−0.0035 (15)	0.0009 (14)
CA_8	0.025 (2)	0.032 (2)	0.025 (2)	−0.0017 (18)	−0.0002 (18)	0.0021 (17)
C_8	0.030 (2)	0.027 (2)	0.0182 (19)	−0.0013 (18)	0.0003 (18)	−0.0010 (16)
O_8	0.0352 (18)	0.0449 (18)	0.0264 (16)	−0.0049 (16)	−0.0040 (14)	0.0104 (14)
CB_8	0.036 (2)	0.032 (2)	0.027 (2)	0.001 (2)	0.000 (2)	0.0014 (18)
CG_8	0.032 (2)	0.041 (2)	0.032 (2)	0.001 (2)	0.000 (2)	−0.002 (2)
CD_8	0.037 (3)	0.032 (2)	0.029 (2)	0.007 (2)	−0.001 (2)	−0.0007 (18)
OE1_8	0.044 (2)	0.0410 (18)	0.0395 (18)	0.0003 (17)	−0.0104 (17)	0.0070 (15)
NE2_8	0.035 (2)	0.052 (3)	0.041 (2)	−0.006 (2)	−0.003 (2)	−0.001 (2)
N_9	0.0279 (19)	0.0324 (18)	0.0141 (15)	−0.0017 (16)	−0.0009 (14)	0.0017 (14)
CA_9	0.032 (2)	0.033 (2)	0.0149 (18)	−0.0038 (19)	0.0031 (17)	−0.0003 (16)
C_9	0.027 (2)	0.028 (2)	0.0209 (19)	−0.0012 (18)	−0.0032 (17)	0.0011 (16)
O_9	0.052 (2)	0.0347 (16)	0.0231 (15)	−0.0083 (17)	−0.0036 (15)	0.0058 (13)
CB_9	0.027 (2)	0.039 (2)	0.025 (2)	−0.002 (2)	0.0026 (18)	−0.0019 (18)
CG_9	0.036 (3)	0.036 (2)	0.031 (2)	0.006 (2)	0.004 (2)	−0.0012 (19)
CD1_9	0.043 (3)	0.036 (3)	0.053 (3)	0.003 (2)	−0.003 (3)	−0.014 (2)
CD2_9	0.048 (3)	0.038 (3)	0.037 (3)	0.015 (3)	0.004 (2)	0.001 (2)
N_10	0.056 (3)	0.0244 (18)	0.0198 (17)	−0.0001 (19)	0.0026 (18)	0.0012 (14)
CA_10	0.048 (3)	0.027 (2)	0.028 (2)	−0.001 (2)	0.004 (2)	−0.0043 (18)
C_10	0.060 (3)	0.027 (2)	0.032 (2)	0.003 (2)	0.011 (2)	−0.0039 (19)
O_10	0.111 (4)	0.0328 (18)	0.055 (2)	0.018 (2)	0.046 (3)	0.0111 (17)
CB_10	0.053 (4)	0.061 (4)	0.048 (3)	−0.016 (3)	0.001 (3)	−0.016 (3)
CG1_10	0.051 (4)	0.086 (5)	0.072 (5)	−0.010 (4)	0.010 (4)	−0.015 (4)
CG2_10	0.070 (5)	0.063 (4)	0.092 (6)	0.006 (4)	−0.002 (4)	−0.036 (4)
CD1_10	0.063 (5)	0.083 (6)	0.128 (8)	0.005 (5)	0.009 (5)	−0.023 (6)
N_11	0.064 (3)	0.0314 (19)	0.032 (2)	0.013 (2)	0.012 (2)	0.0091 (17)
CA_11	0.061 (4)	0.045 (3)	0.034 (3)	0.022 (3)	0.009 (3)	0.012 (2)
C_11	0.065 (4)	0.034 (2)	0.032 (3)	0.011 (3)	0.005 (3)	−0.008 (2)
O_11	0.065 (3)	0.116 (4)	0.043 (2)	−0.016 (3)	0.014 (2)	−0.016 (3)
CB_11	0.045 (4)	0.028 (3)	0.024 (3)	0.004 (3)	−0.006 (3)	−0.004 (3)
CG_11	0.059 (5)	0.028 (3)	0.027 (4)	0.013 (4)	0.002 (4)	0.008 (3)
CD_11	0.052 (6)	0.043 (5)	0.020 (4)	0.006 (5)	−0.003 (4)	−0.001 (3)
OE1_11	0.081 (5)	0.041 (3)	0.027 (3)	0.023 (3)	−0.010 (3)	0.007 (2)
C_12	0.168 (10)	0.061 (4)	0.069 (5)	0.036 (6)	0.041 (6)	0.025 (4)
C1_12	0.200 (13)	0.074 (5)	0.082 (6)	0.055 (7)	0.043 (8)	0.014 (5)
O_12	0.186 (7)	0.066 (3)	0.069 (3)	0.041 (4)	0.054 (4)	0.035 (3)
O1_12	0.188 (7)	0.070 (3)	0.074 (3)	0.060 (4)	0.056 (4)	0.033 (3)
C2_12	0.147 (10)	0.088 (6)	0.068 (5)	0.038 (6)	0.047 (6)	0.024 (4)
C3_12	0.104 (7)	0.072 (5)	0.105 (7)	0.034 (5)	0.016 (6)	0.003 (5)
O1_13	0.059 (2)	0.0319 (17)	0.0187 (15)	0.0045 (18)	−0.0026 (16)	−0.0022 (13)
O1_14	0.047 (2)	0.037 (2)	0.052 (2)	0.0053 (19)	0.0148 (19)	0.004 (2)

Geometric parameters (Å, º)

C3—C2	1.488 (11)	CA_5—C_5	1.516 (8)
C3—C4	1.521 (13)	C_5—O_5	1.226 (6)
C4—C5	1.484 (13)	C_5—N_6	1.352 (7)
C5—C6	1.524 (15)	N_6—CA_6	1.455 (7)
C6—C7	1.526 (16)	CA_6—CB_6	1.498 (8)
C7—C8	1.495 (14)	CA_6—C_6	1.526 (7)
C8—C9	1.476 (16)	C_6—O_6	1.229 (6)
C3'—C4'	1.54 (3)	C_6—N_7	1.340 (6)
C3'—C2	1.57 (2)	CB_6—OG_6	1.424 (7)
C4'—C5'	1.65 (3)	N_7—CA_7	1.454 (6)
C5'—C6'	1.58 (4)	CA_7—C_7	1.532 (6)
C6'—C7'	1.38 (5)	CA_7—CB_7	1.533 (7)
C7'—C8'	1.59 (4)	C_7—O_7	1.231 (5)
C8'—C9'	1.51 (5)	C_7—N_8	1.335 (6)
O—C	1.246 (6)	CB_7—CG_7	1.523 (7)
C—N_1	1.336 (6)	CG_7—CD2_7	1.504 (8)
C—C1	1.519 (7)	CG_7—CD1_7	1.550 (10)
C1—C2	1.503 (7)	N_8—CA_8	1.456 (5)
C2—O1	1.439 (6)	CA_8—CB_8	1.527 (6)
N_1—CA_1	1.471 (6)	CA_8—C_8	1.525 (6)
CA_1—C_1	1.503 (7)	C_8—O_8	1.231 (5)
CA_1—CB_1	1.544 (7)	C_8—N_9	1.333 (6)
C_1—O_1	1.245 (5)	CB_8—CG_8	1.533 (7)
C_1—N_2	1.335 (6)	CG_8—CD_8	1.520 (7)
CB_1—CG_1	1.536 (9)	CD_8—OE1_8	1.235 (6)
CG_1—CD2_1	1.530 (11)	CD_8—NE2_8	1.326 (7)
CG_1—CD1_1	1.535 (9)	N_9—CA_9	1.461 (6)
N_2—CA_2	1.447 (6)	CA_9—C_9	1.525 (6)
CA_2—CB_2	1.516 (7)	CA_9—CB_9	1.533 (7)
CA_2—C_2	1.532 (6)	C_9—O_9	1.241 (5)
C_2—O_2	1.226 (6)	C_9—N_10	1.338 (5)
C_2—N_3	1.333 (6)	CB_9—CG_9	1.538 (7)
CB_2—CG_2	1.509 (7)	CG_9—CD1_9	1.504 (7)
CG_2—OD2_2	1.208 (6)	CG_9—CD2_9	1.513 (7)
CG_2—OD1_2	1.324 (6)	N_10—CA_10	1.426 (6)
N_3—CA_3	1.448 (5)	CA_10—C_10	1.508 (7)
CA_3—C_3	1.533 (6)	CA_10—CB_10	1.556 (8)
CA_3—CB_3	1.535 (6)	C_10—O_10	1.230 (6)
C_3—O_3	1.244 (5)	C_10—N_11	1.335 (6)
C_3—N_4	1.327 (7)	CB_10—CG2_10	1.476 (9)
CB_3—OG1_3	1.455 (6)	CB_10—CG1_10	1.559 (9)
CB_3—CG2_3	1.492 (7)	CG1_10—CD1_10	1.545 (11)
OG1_3—C_11	1.336 (7)	N_11—CA_11	1.461 (6)
N_4—CA_4	1.469 (6)	CA_11—C_11	1.516 (7)
CA_4—CB_4	1.524 (7)	CA_11—CB_11'	1.519 (12)
CA_4—C_4	1.529 (7)	CA_11—CB_11	1.585 (8)
C_4—O_4	1.247 (5)	C_11—O_11	1.207 (7)
C_4—N_5	1.335 (6)	CB_11—CG_11	1.513 (9)
CB_4—CG_4	1.507 (10)	CG_11—CD_11	1.544 (12)
CG_4—CD2_4	1.364 (14)	CD_11—OE1_11	1.226 (12)
CG_4—CD1_4	1.561 (13)	CD_11—OE2_11	1.289 (10)
CB_5—CG_5	1.564 (14)	CB_11'—CG_11'	1.494 (16)
CB_5—CA_5	1.575 (12)	CG_11'—CD_11'	1.508 (15)
CG_5—CD2_5	1.508 (11)	CD_11'—OE1_11'	1.238 (14)
CG_5—CD1_5	1.541 (9)	CD_11'—OE2_11'	1.268 (16)
CB_5'—CA_5	1.36 (4)	C_12—O_12	1.197 (9)
CB_5'—CG_5'	1.57 (6)	C_12—O1_12	1.318 (9)
CG_5'—CD2_5'	1.37 (5)	C_12—C1_12	1.499 (12)
CG_5'—CD1_5'	1.69 (5)	O1_12—C2_12	1.443 (10)
N_5—CA_5	1.472 (6)	C2_12—C3_12	1.432 (11)
C2—C3—C4	112.6 (7)	O_5—C_5—N_6	121.7 (5)
C5—C4—C3	113.5 (8)	O_5—C_5—CA_5	120.7 (5)
C4—C5—C6	112.6 (9)	N_6—C_5—CA_5	117.5 (4)
C5—C6—C7	115.6 (10)	C_5—N_6—CA_6	120.6 (4)
C8—C7—C6	116.2 (9)	N_6—CA_6—CB_6	111.7 (4)
C9—C8—C7	115.8 (10)	N_6—CA_6—C_6	111.7 (4)
C4'—C3'—C2	115.2 (15)	CB_6—CA_6—C_6	107.8 (4)
C3'—C4'—C5'	112.2 (17)	O_6—C_6—N_7	122.0 (4)
C6'—C5'—C4'	107 (2)	O_6—C_6—CA_6	119.9 (5)
C7'—C6'—C5'	120 (3)	N_7—C_6—CA_6	117.9 (4)
C6'—C7'—C8'	119 (3)	OG_6—CB_6—CA_6	113.2 (5)
C9'—C8'—C7'	114 (3)	C_6—N_7—CA_7	122.0 (4)
O—C—N_1	121.7 (4)	N_7—CA_7—C_7	112.8 (4)
O—C—C1	122.4 (5)	N_7—CA_7—CB_7	109.0 (4)
N_1—C—C1	115.8 (4)	C_7—CA_7—CB_7	112.2 (4)
C2—C1—C	115.0 (4)	O_7—C_7—N_8	122.6 (4)
O1—C2—C3	111.6 (5)	O_7—C_7—CA_7	119.8 (4)
O1—C2—C1	108.6 (4)	N_8—C_7—CA_7	117.5 (4)
C3—C2—C1	118.1 (6)	CG_7—CB_7—CA_7	113.1 (4)
O1—C2—C3'	103.6 (8)	CD2_7—CG_7—CB_7	110.9 (5)
C3—C2—C3'	22.4 (7)	CD2_7—CG_7—CD1_7	110.5 (6)
C1—C2—C3'	103.8 (8)	CB_7—CG_7—CD1_7	108.5 (6)
C—N_1—CA_1	120.6 (4)	C_7—N_8—CA_8	121.0 (4)
N_1—CA_1—C_1	111.5 (4)	N_8—CA_8—CB_8	109.3 (4)
N_1—CA_1—CB_1	109.8 (4)	N_8—CA_8—C_8	113.1 (4)
C_1—CA_1—CB_1	109.7 (4)	CB_8—CA_8—C_8	110.3 (4)
O_1—C_1—N_2	121.8 (5)	O_8—C_8—N_9	123.4 (4)
O_1—C_1—CA_1	120.1 (5)	O_8—C_8—CA_8	119.5 (4)
N_2—C_1—CA_1	118.0 (4)	N_9—C_8—CA_8	117.1 (4)
CG_1—CB_1—CA_1	116.0 (5)	CA_8—CB_8—CG_8	112.4 (4)
CD2_1—CG_1—CD1_1	110.4 (6)	CD_8—CG_8—CB_8	112.7 (4)
CD2_1—CG_1—CB_1	113.9 (5)	OE1_8—CD_8—NE2_8	122.6 (5)
CD1_1—CG_1—CB_1	109.0 (6)	OE1_8—CD_8—CG_8	120.3 (5)
C_1—N_2—CA_2	121.4 (4)	NE2_8—CD_8—CG_8	117.0 (4)
N_2—CA_2—CB_2	112.3 (4)	C_8—N_9—CA_9	123.1 (3)
N_2—CA_2—C_2	112.7 (4)	N_9—CA_9—C_9	109.7 (4)
CB_2—CA_2—C_2	111.3 (4)	N_9—CA_9—CB_9	110.7 (3)
O_2—C_2—N_3	122.3 (4)	C_9—CA_9—CB_9	110.9 (4)
O_2—C_2—CA_2	119.7 (4)	O_9—C_9—N_10	123.2 (4)
N_3—C_2—CA_2	118.0 (4)	O_9—C_9—CA_9	123.0 (4)
CG_2—CB_2—CA_2	115.4 (4)	N_10—C_9—CA_9	113.9 (4)
OD2_2—CG_2—OD1_2	125.2 (5)	CA_9—CB_9—CG_9	114.2 (4)
OD2_2—CG_2—CB_2	124.8 (4)	CD1_9—CG_9—CD2_9	111.6 (4)
OD1_2—CG_2—CB_2	110.0 (4)	CD1_9—CG_9—CB_9	112.6 (4)
C_2—N_3—CA_3	120.3 (4)	CD2_9—CG_9—CB_9	110.0 (4)
N_3—CA_3—C_3	110.1 (4)	C_9—N_10—CA_10	126.3 (4)
N_3—CA_3—CB_3	109.7 (4)	N_10—CA_10—C_10	106.7 (4)
C_3—CA_3—CB_3	113.2 (4)	N_10—CA_10—CB_10	109.9 (5)
O_3—C_3—N_4	121.5 (4)	C_10—CA_10—CB_10	111.4 (4)
O_3—C_3—CA_3	120.5 (4)	O_10—C_10—N_11	121.1 (5)
N_4—C_3—CA_3	117.9 (4)	O_10—C_10—CA_10	120.0 (4)
OG1_3—CB_3—CG2_3	107.5 (4)	N_11—C_10—CA_10	118.9 (4)
OG1_3—CB_3—CA_3	105.4 (4)	CG2_10—CB_10—CA_10	114.0 (6)
CG2_3—CB_3—CA_3	112.0 (5)	CG2_10—CB_10—CG1_10	111.6 (6)
C_11—OG1_3—CB_3	117.4 (5)	CA_10—CB_10—CG1_10	109.6 (5)
C_3—N_4—CA_4	118.8 (4)	CD1_10—CG1_10—CB_10	114.0 (7)
N_4—CA_4—CB_4	111.2 (4)	C_10—N_11—CA_11	118.7 (4)
N_4—CA_4—C_4	110.6 (4)	N_11—CA_11—C_11	110.7 (4)
CB_4—CA_4—C_4	110.5 (4)	N_11—CA_11—CB_11'	111.4 (7)
O_4—C_4—N_5	122.1 (4)	C_11—CA_11—CB_11'	125.3 (7)
O_4—C_4—CA_4	120.9 (4)	N_11—CA_11—CB_11	110.5 (5)
N_5—C_4—CA_4	117.0 (4)	C_11—CA_11—CB_11	101.3 (4)
CG_4—CB_4—CA_4	115.1 (5)	CB_11—CA_11—CB_11'	30.6 (6)
CD2_4—CG_4—CB_4	119.5 (8)	O_11—C_11—OG1_3	126.0 (5)
CD2_4—CG_4—CD1_4	116.2 (9)	O_11—C_11—CA_11	124.6 (6)
CB_4—CG_4—CD1_4	107.3 (8)	OG1_3—C_11—CA_11	109.3 (5)
CG_5—CB_5—CA_5	113.5 (8)	CG_11—CB_11—CA_11	109.3 (5)
CD2_5—CG_5—CD1_5	111.4 (6)	CB_11—CG_11—CD_11	113.0 (6)
CD2_5—CG_5—CB_5	114.1 (8)	OE1_11—CD_11—OE2_11	125.8 (10)
CD1_5—CG_5—CB_5	106.7 (7)	OE1_11—CD_11—CG_11	119.9 (7)
CA_5—CB_5'—CG_5'	119 (4)	OE2_11—CD_11—CG_11	114.3 (8)
CD2_5'—CG_5'—CB_5'	120 (4)	CG_11'—CB_11'—CA_11	107.5 (11)
CD2_5'—CG_5'—CD1_5'	107 (4)	CB_11'—CG_11'—CD_11'	114.7 (12)
CB_5'—CG_5'—CD1_5'	103 (3)	OE1_11'—CD_11'—OE2_11'	127.2 (16)
C_4—N_5—CA_5	121.8 (4)	OE1_11'—CD_11'—CG_11'	114.2 (13)
CB_5—CA_5—N_5	109 (2)	OE2_11'—CD_11'—CG_11'	118.6 (15)
CB_5'—CA_5—C_5	116 (2)	O_12—C_12—O1_12	122.1 (8)
N_5—CA_5—C_5	114.1 (4)	O_12—C_12—C1_12	125.3 (7)
CB_5—CA_5—CB_5'	6 (3)	O1_12—C_12—C1_12	112.6 (7)
N_5—CA_5—CB_5'	108.3 (5)	C_12—O1_12—C2_12	119.7 (6)
C_5—CA_5—CB_5	111.1 (7)	C3_12—C2_12—O1_12	108.8 (7)