Cyclic lipoundecapeptide amphisin from Pseudomonas sp. strain DSS73

The crystal structure of the lipoundecapeptide amphisin, presented here as the tetrahydrate, C₆₆H₁₁₄N₁₂O₂₀·4H₂O, originating from non-ribosomal biosynthesis by Pseudomonas sp. strain DSS73, has been solved to a resolution of 0.65 Å. The primary structure of amphisin 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-Asp (Leu is leucine, Asp is aspartic acid, Thr is threonine, Ser is serine, Gln is glut­amine and Ile is isoleucine). The peptide is a lactone, linking Thr4 O_γ to the C-terminal. The stereochemistry of the β-hydroxy acid is R. The peptide is a close analogue of the cyclic lipopeptides tensin and pholipeptin produced by Pseudomonas fluorescens. The structure of amphisin is mainly helical (3₁₀-helix), with the cyclic peptide wrapping around a hydrogen-bonded water mol­ecule. This lipopeptide is amphiphilic and has biosurfactant and antifungal properties.

S1. Comment

A rich variety of of bioactive extracellular low-molecular-weight compounds are produced by bacteria. They may be classified as siderophores, antibiotics or toxins according to their biological activities. From a biosynthetic viewpoint, some of these are peptides produced non-ribosomally by large multifunctional peptide synthethases (Marahiel et al., 1997). 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). This non-ribosomal synthetic route utilizing L–, D– and modified amino acids is able to produce a broad diversity of specialized peptides (Konz & Marahiel, 1999). Genetic engineering of the peptide synthethases has been successfully applied to produce modified peptides (Schneider et al., 1998).

Bacillus subtilis has traditionally been a source of bioactive peptides, especially the cyclic lipopeptide 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 isolated from Bacillus cereus and characterized (Umezawa et al., 1986). All of these compounds are amphiphilic membrane-active biosurfactants with specific antimicrobial activities, and fengycin and the plipstatins inhibit phospholipase A2 (Umezawa et al., 1986). Pseudomonas flourescens also produces a number of cyclic lipopeptides with biosurfactant and antifungal properties e.g. viscosinamide (Nielsen et al., 1999) and tensin (Nielsen et al., 2000). Pseudomonas fluorescens was the source of the phospholipase C inhibitor pholipeptin (Ui et al., 1997), and another Pseudomonas sp. yielded the antimycobacterial massetolides (Gerard et al., 1997). The present study is part of our research program to discover and describe novel cyclic lipopeptides from various soil-associated Pseudomonas strains with a particular emphasis on their biosurfactant and antifungal properties.

The few crystal structures of cyclic lipopeptides comprise tensin (Henriksen et al., 2000) and the white-line-inducing principle (WLIP) from Pseudomonas reactans (Han et al., 1992). In this paper, we present the structure of amphisin tetrahydrate, (I), a cyclic lipopeptide with 11 amino acids, a β-hydroxydecanoyl-N-terminal and a lactone formation between the side chain of Thr4 and the C-terminal. Close analogy exists between amphisin and the structurally related tensin, which differs only by incorporating Glu12 in place of Asp12.

The structure of amphisin is shown in Fig. 1. The absolute configuration was substantiated by chiral gas chromatographic analysis of the constituents in the hydrolyzed peptide. Asp3 has a disordered side chain and minor disorder was observed around residues Leu10 and Leu8 (not included in the model), but unlike the structure of tensin, the lipid shows no sign of disorder. The peptide incorporates a helical motif (3₁₀-helix from Leu2 to Leu8). The cyclic part of the peptide forms a `cobra-head'-like backbone around a water molecule. The coordination of the water is almost planar, accepting one and donating two peptide hydrogen bonds. Three additional water molecules are found in the crystal structure.

The molecule has both a hydrophobic and a hydrophilic side, in agreement with its function as a biosurfactant. With exception of Leu6, the hydrophobic side chains in the ring are aligned in a parallel formation. The alternating stereo-configurations of the amino acids are required for this organization. The two acidic residues, charged at high pH, are situated on the hydrophilic side of the molecule, quite far apart and facing opposite directions. The peptide backbones of amphisin and tensin are similar and not affected by the amino acid substitution. Interestingly, WLIP shares some of the `cobra-head' features of amphisin and tensin even though WLIP contains two amino acids less than the latter. It is common, however, that these cyclic lipopeptides can adopt a number of distinct and different conformations. The conformation of WLIP in the crystal structure is thus significantly different from the one deduced by NMR in dimethyl sulfoxide solution (Mortishire-Smith et al., 1991). Another example is surfactin, where NMR studies revealed two very different conformations (Bonmatin et al., 1994). The conformation of surfactin has furthermore been shown to be highly dependent on the nature of the solvent (Itokawa et al., 1994). The amphiphilic property combined with conformational flexibility could be of crucial importance in the interaction with biological membranes or receptor sites.

S2. Experimental

Amphisin (10 mg) was isolated from the EtOAc extract of 50 Petri dishes with potato dextrose agar (PDA) medium incubated with Pseudomonas strain DSS73 at 298 K for 4 d. Various types of Sephadex LH-20, Si-60 and RP-18-based chromatography were used to purify the compound. Final crystallization occurred overnight from a 278 K solution of CH₃CN/H₂O (70:30) + 0.5% TFA.

S3. Refinement

All ordered and major conformation (occupancy ~0.7) non-H atoms were refined with anisotropic displacement parameters. All H atoms were located in difference Fourier maps and treated as riding on the appropiate heavy atoms (C—H = 0.00–0.00 Å). The Asp3 residue was found to have more than one conformation.

Computing details

Data collection: XPRESS (MacScience, 1989); cell refinement: DENZO (Otwinowski & Minor, 1997); data reduction: DENZO; 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 amphisin. Only the most occupied sites of Asp3 are drawn. The lipid is attached to the N-terminal, while the C-terminal forms a lactone with the Thr4 side chain. The molecule is viewed from the side, showing the amphiphilic arrangement of side chains and the central hydrogen-bonded water molecule.

R-β-hydroxydecanoyl-D-Leu-D-Asp-D-allo-Thr-D-Leu-D-Leu-D-Ser-L-Leu- D-Gln-L-Leu-L-Ile-L-Asp tetrahydrate

Crystal data

C66H114N12O20·4H2O	F(000) = 3176
Mr = 1467.76	Dx = 1.232 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71075 Å
a = 12.329 (10) Å	µ = 0.09 mm^−1
b = 20.245 (10) Å	T = 293 K
c = 31.691 (10) Å	Prism, colourless
V = 7910 (8) Å^3	0.3 × 0.2 × 0.1 mm
Z = 4

Data collection

Nonius KappaCCD diffractometer	8726 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.037
Graphite monochromator	θmax = 27.4°, θmin = 1.2°
ω scans	h = −15→15
71388 measured reflections	k = −26→26
9869 independent reflections	l = −41→41

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.157	H-atom parameters constrained
S = 0.86	w = 1/[σ^2(Fo^2) + (0.155P)^2 + 1.0565P] where P = (Fo^2 + 2Fc^2)/3
9869 reflections	(Δ/σ)max = 0.053
941 parameters	Δρmax = 0.56 e Å^−3
0 restraints	Δρmin = −0.52 e Å^−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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
O_1	−0.32266 (16)	−1.12882 (10)	−0.28841 (6)	0.0213 (4)
C_1	−0.3035 (2)	−1.15012 (12)	−0.32424 (8)	0.0164 (5)
C1_1	−0.1941 (2)	−1.14004 (14)	−0.34460 (9)	0.0203 (5)
H1A_1	−0.1962	−1.1551	−0.3736	0.024*
H1B_1	−0.1396	−1.1655	−0.3297	0.024*
C2_1	−0.1650 (2)	−1.06681 (14)	−0.34322 (8)	0.0193 (5)
H2_1	−0.1572	−1.0541	−0.3135	0.023*
O2_1	−0.25301 (18)	−1.02896 (10)	−0.36085 (7)	0.0277 (5)
H2A_1	−0.2518	−1.0472	−0.3923	0.050*
C3_1	−0.0583 (2)	−1.05179 (16)	−0.36540 (9)	0.0248 (6)
H3A_1	−0.0665	−1.0601	−0.3954	0.030*
H3B_1	−0.0027	−1.0814	−0.3548	0.030*
C4_1	−0.0212 (3)	−0.98050 (16)	−0.35900 (9)	0.0266 (6)
H4A_1	−0.0837	−0.9516	−0.3610	0.032*
H4B_1	0.0285	−0.9687	−0.3815	0.032*
C5_1	0.0348 (2)	−0.96882 (14)	−0.31649 (9)	0.0233 (6)
H5A_1	−0.0141	−0.9818	−0.2940	0.028*
H5B_1	0.0985	−0.9968	−0.3148	0.028*
C6_1	0.0690 (2)	−0.89727 (14)	−0.30956 (9)	0.0242 (6)
H6A_1	0.1184	−0.8844	−0.3319	0.029*
H6B_1	0.0054	−0.8692	−0.3115	0.029*
C7_1	0.1237 (3)	−0.88574 (15)	−0.26724 (9)	0.0251 (6)
H7A_1	0.1874	−0.9137	−0.2654	0.030*
H7B_1	0.0744	−0.8989	−0.2449	0.030*
C8_1	0.1577 (3)	−0.81440 (16)	−0.25998 (11)	0.0335 (7)
H8A_1	0.0933	−0.7871	−0.2581	0.040*
H8B_1	0.1995	−0.7994	−0.2840	0.040*
C9_1	0.2249 (4)	−0.8054 (2)	−0.22010 (12)	0.0459 (9)
H9A_1	0.2454	−0.7599	−0.2174	0.069*
H9B_1	0.2889	−0.8323	−0.2218	0.069*
H9C_1	0.1828	−0.8184	−0.1960	0.069*
N_2	−0.38008 (19)	−1.18151 (11)	−0.34695 (7)	0.0167 (4)
H0_2	−0.3664	−1.1935	−0.3724	0.020*
CA_2	−0.4868 (2)	−1.19532 (13)	−0.32846 (8)	0.0165 (5)
HA_2	−0.4779	−1.2288	−0.3064	0.020*
C_2	−0.5370 (2)	−1.13419 (12)	−0.30877 (8)	0.0152 (5)
O_2	−0.57539 (16)	−1.13561 (9)	−0.27297 (6)	0.0194 (4)
CB_2	−0.5644 (2)	−1.22235 (13)	−0.36197 (8)	0.0188 (5)
HB1_2	−0.5367	−1.2643	−0.3721	0.023*
HB2_2	−0.5659	−1.1920	−0.3857	0.023*
CG_2	−0.6808 (3)	−1.23242 (14)	−0.34593 (10)	0.0254 (6)
HG_2	−0.7050	−1.1907	−0.3334	0.030*
CD1_2	−0.6854 (3)	−1.28581 (17)	−0.31146 (13)	0.0430 (9)
HD1A_2	−0.6371	−1.2742	−0.2889	0.065*
HD1B_2	−0.6639	−1.3275	−0.3232	0.065*
HD1C_2	−0.7581	−1.2891	−0.3008	0.065*
CD2_2	−0.7560 (3)	−1.2484 (2)	−0.38189 (13)	0.0465 (10)
HD2A_2	−0.7515	−1.2143	−0.4028	0.070*
HD2B_2	−0.8291	−1.2513	−0.3716	0.070*
HD2C_2	−0.7355	−1.2899	−0.3942	0.070*
N_3	−0.54510 (18)	−1.08018 (10)	−0.33354 (7)	0.0157 (4)
H0_3	−0.5123	−1.0777	−0.3574	0.019*
CA_3	−0.6119 (2)	−1.02637 (13)	−0.31793 (8)	0.0170 (5)
HA_3	−0.6785	−1.0463	−0.3069	0.020*
C_3	−0.5582 (2)	−0.98998 (12)	−0.28106 (8)	0.0161 (5)
O_3	−0.61337 (17)	−0.96166 (11)	−0.25439 (7)	0.0264 (5)
CB_3	−0.6453 (3)	−0.98066 (16)	−0.35300 (10)	0.0278 (6)
HB1_3	−0.5831	−0.9696	−0.3703	0.033*
HB2_3	−0.6750	−0.9401	−0.3414	0.033*
CG_3	−0.7329 (3)	−1.0169 (2)	−0.38004 (12)	0.0210 (8)	0.797 (7)
OD1_3	−0.7664 (2)	−0.97852 (17)	−0.41095 (9)	0.0342 (9)	0.797 (7)
OD2_3	−0.7662 (3)	−1.07143 (15)	−0.37368 (11)	0.0355 (9)	0.797 (7)
CGA_3	−0.7134 (13)	−0.9805 (9)	−0.3879 (5)	0.023 (3)*	0.203 (7)
OD1A_3	−0.7541 (11)	−0.9339 (7)	−0.4060 (4)	0.038 (4)*	0.203 (7)
OD2A_3	−0.7411 (11)	−1.0411 (7)	−0.3946 (5)	0.030 (3)*	0.203 (7)
N_4	−0.44841 (17)	−0.99130 (10)	−0.27976 (6)	0.0140 (4)
H0_4	−0.4116	−1.0061	−0.3008	0.017*
CA_4	−0.3945 (2)	−0.96718 (12)	−0.24217 (7)	0.0132 (5)
HA_4	−0.4222	−0.9228	−0.2361	0.016*
C_4	−0.4189 (2)	−1.01158 (13)	−0.20367 (8)	0.0146 (5)
O_4	−0.44843 (16)	−0.98742 (9)	−0.16977 (6)	0.0191 (4)
CB_4	−0.2725 (2)	−0.96176 (13)	−0.25061 (8)	0.0146 (5)
HB_4	−0.2434	−1.0046	−0.2594	0.018*
OG1_4	−0.22580 (15)	−0.94216 (9)	−0.21044 (6)	0.0170 (4)
CG2_4	−0.2462 (2)	−0.90968 (14)	−0.28315 (9)	0.0214 (5)
HG2A_4	−0.1692	−0.9082	−0.2875	0.032*
HG2B_4	−0.2710	−0.8674	−0.2734	0.032*
HG2C_4	−0.2816	−0.9203	−0.3092	0.032*
N_5	−0.40990 (18)	−1.07649 (11)	−0.20932 (7)	0.0150 (4)
H0_5	−0.3883	−1.0913	−0.2333	0.018*
CA_5	−0.4359 (2)	−1.12336 (12)	−0.17554 (8)	0.0150 (5)
HA_5	−0.3826	−1.1185	−0.1528	0.018*
C_5	−0.5498 (2)	−1.11129 (12)	−0.15760 (8)	0.0153 (5)
O_5	−0.56694 (16)	−1.11360 (10)	−0.11907 (6)	0.0200 (4)
CB_5	−0.4259 (2)	−1.19329 (13)	−0.19443 (9)	0.0196 (5)
HB1_5	−0.4713	−1.1955	−0.2194	0.023*
HB2_5	−0.3515	−1.1997	−0.2035	0.023*
CG_5	−0.4567 (3)	−1.25024 (14)	−0.16560 (9)	0.0230 (6)
HG_5	−0.5285	−1.2411	−0.1536	0.028*
CD1_5	−0.3763 (3)	−1.25853 (17)	−0.12918 (11)	0.0374 (8)
HD1A_5	−0.3992	−1.2943	−0.1114	0.056*
HD1B_5	−0.3736	−1.2185	−0.1130	0.056*
HD1C_5	−0.3055	−1.2679	−0.1403	0.056*
CD2_5	−0.4644 (3)	−1.31336 (15)	−0.19210 (11)	0.0350 (7)
HD2A_5	−0.4850	−1.3497	−0.1743	0.053*
HD2B_5	−0.3952	−1.3224	−0.2047	0.053*
HD2C_5	−0.5177	−1.3075	−0.2138	0.053*
N_6	−0.62942 (18)	−1.10036 (11)	−0.18579 (7)	0.0159 (4)
H0_6	−0.6136	−1.0983	−0.2122	0.019*
CA_6	−0.7419 (2)	−1.09187 (13)	−0.17267 (8)	0.0165 (5)
HA_6	−0.7603	−1.1287	−0.1539	0.020*
C_6	−0.7609 (2)	−1.02767 (14)	−0.14815 (8)	0.0182 (5)
O_6	−0.84672 (16)	−1.01923 (12)	−0.12897 (7)	0.0261 (4)
CB_6	−0.8194 (2)	−1.09442 (13)	−0.21043 (8)	0.0189 (5)
HB1_6	−0.8001	−1.0591	−0.2297	0.023*
HB2_6	−0.8922	−1.0856	−0.2004	0.023*
CG_6	−0.8208 (2)	−1.15991 (14)	−0.23525 (9)	0.0224 (6)
HG_6	−0.7511	−1.1642	−0.2498	0.027*
CD1_6	−0.8355 (4)	−1.22050 (16)	−0.20723 (12)	0.0395 (8)
HD1A_6	−0.7791	−1.2216	−0.1863	0.059*
HD1B_6	−0.8318	−1.2597	−0.2242	0.059*
HD1C_6	−0.9048	−1.2184	−0.1935	0.059*
CD2_6	−0.9098 (4)	−1.15624 (19)	−0.26867 (14)	0.0480 (10)
HD2A_6	−0.8992	−1.1176	−0.2858	0.072*
HD2B_6	−0.9793	−1.1538	−0.2551	0.072*
HD2C_6	−0.9069	−1.1949	−0.2861	0.072*
N_7	−0.68199 (18)	−0.98228 (12)	−0.14790 (7)	0.0181 (4)
H0_7	−0.6235	−0.9893	−0.1620	0.022*
CA_7	−0.6935 (2)	−0.92116 (14)	−0.12413 (9)	0.0199 (5)
HA_7	−0.7601	−0.8990	−0.1333	0.024*
C_7	−0.6997 (2)	−0.93170 (14)	−0.07652 (8)	0.0194 (5)
O_7	−0.73193 (19)	−0.88621 (11)	−0.05389 (7)	0.0283 (5)
CB_7	−0.5975 (2)	−0.87501 (14)	−0.13239 (9)	0.0240 (6)
HB1_7	−0.5836	−0.8733	−0.1625	0.029*
HB2_7	−0.6163	−0.8308	−0.1232	0.029*
OG_7	−0.50137 (17)	−0.89569 (11)	−0.11115 (7)	0.0226 (4)
HG_7	−0.474 (4)	−0.921 (2)	−0.1255 (14)	0.035 (11)*
N_8	−0.66289 (19)	−0.98932 (12)	−0.06125 (7)	0.0184 (4)
H0_8	−0.6387	−1.0188	−0.0783	0.022*
CA_8	−0.6634 (2)	−1.00244 (15)	−0.01614 (8)	0.0205 (5)
HA_8	−0.7336	−0.9881	−0.0049	0.025*
C_8	−0.5755 (2)	−0.96517 (16)	0.00736 (9)	0.0249 (6)
O_8	−0.5775 (2)	−0.96377 (17)	0.04630 (7)	0.0485 (8)
CB_8	−0.6523 (2)	−1.07687 (16)	−0.00779 (10)	0.0267 (6)
HB1_8	−0.5887	−1.0929	−0.0226	0.032*
HB2_8	−0.6399	−1.0835	0.0221	0.032*
CG_8	−0.7501 (3)	−1.11855 (16)	−0.02112 (11)	0.0353 (7)
HG_8	−0.7655	−1.1101	−0.0510	0.042*
CD1_8	−0.7220 (6)	−1.1915 (2)	−0.0156 (3)	0.094 (2)
HD1A_8	−0.6587	−1.2018	−0.0320	0.142*
HD1B_8	−0.7817	−1.2181	−0.0250	0.142*
HD1C_8	−0.7079	−1.2004	0.0136	0.142*
CD2_8	−0.8490 (3)	−1.1027 (2)	0.00424 (17)	0.0532 (11)
HD2A_8	−0.8659	−1.0567	0.0013	0.080*
HD2B_8	−0.8357	−1.1127	0.0334	0.080*
HD2C_8	−0.9089	−1.1287	−0.0058	0.080*
N_9	−0.49611 (18)	−0.93509 (12)	−0.01434 (7)	0.0181 (4)
H0_9	−0.4934	−0.9388	−0.0414	0.022*
CA_9	−0.4141 (2)	−0.89590 (13)	0.00784 (8)	0.0177 (5)
HA_9	−0.4500	−0.8745	0.0318	0.021*
C_9	−0.3206 (2)	−0.93661 (14)	0.02532 (8)	0.0193 (5)
O_9	−0.25839 (18)	−0.91046 (11)	0.05144 (6)	0.0260 (4)
CB_9	−0.3690 (2)	−0.84127 (14)	−0.02058 (8)	0.0213 (5)
HB1_9	−0.3047	−0.8226	−0.0075	0.026*
HB2_9	−0.3475	−0.8603	−0.0474	0.026*
CG_9	−0.4505 (3)	−0.78645 (15)	−0.02850 (9)	0.0264 (6)
HG1_9	−0.4210	−0.7566	−0.0495	0.032*
HG2_9	−0.5161	−0.8057	−0.0401	0.032*
CD_9	−0.4797 (3)	−0.74710 (16)	0.01054 (9)	0.0286 (6)
OE1_9	−0.4185 (2)	−0.74662 (12)	0.04215 (7)	0.0357 (6)
NE2_9	−0.5712 (3)	−0.71398 (16)	0.00902 (10)	0.0434 (8)
HE2A_9	−0.5914	−0.6907	0.0303	0.052*
HE2B_9	−0.6109	−0.7156	−0.0133	0.052*
N_10	−0.3094 (2)	−0.99837 (13)	0.01194 (7)	0.0226 (5)
H0_10	−0.3553	−1.0140	−0.0059	0.027*
CA_10	−0.2207 (3)	−1.04061 (15)	0.02689 (9)	0.0247 (6)
HA_10	−0.1828	−1.0157	0.0489	0.030*
C_10	−0.1405 (2)	−1.04858 (14)	−0.00967 (10)	0.0246 (6)
O_10	−0.0684 (2)	−1.00835 (14)	−0.01532 (11)	0.0483 (7)
CB_10	−0.2665 (3)	−1.10209 (16)	0.04798 (10)	0.0292 (6)
HB1_10	−0.3059	−1.1276	0.0270	0.035*
HB2_10	−0.3180	−1.0886	0.0694	0.035*
CG_10	−0.1809 (3)	−1.14672 (19)	0.06846 (12)	0.0406 (8)
HG_10	−0.1463	−1.1733	0.0464	0.049*
CD1_10	−0.2369 (5)	−1.1928 (3)	0.09945 (17)	0.0647 (14)
HD1A_10	−0.2926	−1.2171	0.0851	0.097*
HD1B_10	−0.2687	−1.1673	0.1218	0.097*
HD1C_10	−0.1847	−1.2230	0.1110	0.097*
CD2_10	−0.0941 (4)	−1.1082 (2)	0.09162 (13)	0.0505 (10)
HD2A_10	−0.0428	−1.1384	0.1038	0.076*
HD2B_10	−0.1269	−1.0823	0.1135	0.076*
HD2C_10	−0.0574	−1.0795	0.0722	0.076*
N_11	−0.1564 (2)	−1.09914 (13)	−0.03639 (8)	0.0255 (5)
H0_11	−0.2002	−1.1304	−0.0296	0.031*
CA_11	−0.0999 (2)	−1.10160 (16)	−0.07685 (9)	0.0264 (6)
HA_11	−0.0228	−1.0926	−0.0721	0.032*
C_11	−0.1465 (2)	−1.04759 (16)	−0.10520 (9)	0.0261 (6)
O_11	−0.24527 (19)	−1.04154 (15)	−0.11018 (9)	0.0434 (7)
CB_11	−0.1116 (3)	−1.17072 (17)	−0.09670 (10)	0.0317 (7)
HB_11	−0.1877	−1.1842	−0.0943	0.038*
CG1_11	−0.0427 (4)	−1.21991 (19)	−0.07181 (15)	0.0484 (10)
HG1A_11	−0.0620	−1.2166	−0.0422	0.058*
HG1B_11	0.0329	−1.2073	−0.0745	0.058*
CG2_11	−0.0817 (4)	−1.1690 (2)	−0.14340 (13)	0.0543 (12)
HG2A_11	−0.0900	−1.2124	−0.1552	0.081*
HG2B_11	−0.0078	−1.1549	−0.1464	0.081*
HG2C_11	−0.1286	−1.1388	−0.1579	0.081*
CD_11	−0.0548 (5)	−1.2925 (2)	−0.08573 (19)	0.0667 (14)
HD1_11	−0.0088	−1.3199	−0.0687	0.100*
HD2_11	−0.0343	−1.2966	−0.1148	0.100*
HD3_11	−0.1289	−1.3061	−0.0823	0.100*
N_12	−0.07620 (18)	−1.00752 (12)	−0.12438 (7)	0.0194 (5)
H0_12	−0.0076	−1.0133	−0.1212	0.023*
CA_12	−0.1166 (2)	−0.95404 (14)	−0.15068 (8)	0.0189 (5)
HA_12	−0.1822	−0.9361	−0.1375	0.023*
C_12	−0.1470 (2)	−0.98029 (15)	−0.19427 (8)	0.0196 (5)
O_12	−0.1069 (2)	−1.02690 (14)	−0.21150 (7)	0.0422 (7)
CB_12	−0.0326 (2)	−0.89870 (14)	−0.15373 (8)	0.0204 (5)
HB1_12	0.0370	−0.9173	−0.1616	0.024*
HB2_12	−0.0542	−0.8678	−0.1755	0.024*
CG_12	−0.0216 (2)	−0.86246 (13)	−0.11213 (8)	0.0197 (5)
OD1_12	0.05989 (19)	−0.82073 (12)	−0.11218 (7)	0.0302 (5)
OD2_12	−0.0841 (2)	−0.87078 (11)	−0.08297 (6)	0.0282 (5)
HD2_12	−0.0659	−0.8474	−0.0630	0.042*
O_13	−0.40021 (18)	−1.08405 (14)	−0.05718 (7)	0.0364 (6)
H1_13	−0.4576	−1.0982	−0.0767	0.050*
H2_13	−0.3478	−1.0772	−0.0757	0.050*
O_14	−0.2008 (2)	−0.76344 (19)	0.06873 (7)	0.0506 (8)
O_15	−0.4851 (3)	−1.07868 (17)	−0.42234 (8)	0.0582 (9)
H1_15	−0.5292	−1.0811	−0.4498	0.020*
O_16	−0.9094 (3)	−0.9157 (2)	0.00362 (11)	0.0464 (11)	0.760 (7)
OA_16	−0.7999 (9)	−0.8672 (5)	0.0373 (3)	0.036 (3)*	0.240 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O_1	0.0190 (10)	0.0290 (10)	0.0159 (9)	0.0004 (8)	0.0011 (7)	−0.0037 (8)
C_1	0.0149 (12)	0.0164 (11)	0.0178 (11)	0.0032 (9)	0.0007 (10)	0.0005 (9)
C1_1	0.0169 (12)	0.0221 (12)	0.0218 (13)	0.0030 (10)	0.0024 (11)	−0.0030 (10)
C2_1	0.0168 (12)	0.0233 (12)	0.0177 (12)	−0.0017 (10)	−0.0008 (10)	−0.0029 (10)
O2_1	0.0231 (10)	0.0243 (10)	0.0358 (12)	0.0000 (9)	−0.0052 (9)	0.0015 (9)
C3_1	0.0206 (13)	0.0363 (16)	0.0176 (12)	−0.0084 (12)	0.0032 (11)	−0.0072 (11)
C4_1	0.0266 (14)	0.0349 (15)	0.0182 (13)	−0.0103 (13)	0.0007 (11)	0.0005 (11)
C5_1	0.0227 (13)	0.0270 (13)	0.0203 (13)	−0.0054 (11)	−0.0009 (11)	−0.0003 (11)
C6_1	0.0218 (13)	0.0270 (14)	0.0237 (13)	−0.0047 (11)	−0.0006 (11)	0.0006 (11)
C7_1	0.0253 (14)	0.0264 (14)	0.0237 (13)	−0.0032 (12)	−0.0002 (12)	−0.0025 (11)
C8_1	0.0352 (17)	0.0298 (15)	0.0355 (17)	−0.0048 (14)	−0.0051 (14)	−0.0039 (13)
C9_1	0.053 (2)	0.046 (2)	0.0381 (19)	−0.0158 (19)	−0.0074 (18)	−0.0136 (16)
N_2	0.0174 (10)	0.0176 (10)	0.0152 (10)	0.0000 (8)	0.0037 (9)	−0.0018 (8)
CA_2	0.0176 (12)	0.0160 (11)	0.0159 (11)	−0.0009 (10)	0.0031 (10)	−0.0001 (9)
C_2	0.0121 (11)	0.0172 (11)	0.0163 (11)	−0.0043 (9)	−0.0003 (9)	−0.0037 (9)
O_2	0.0197 (9)	0.0231 (9)	0.0154 (8)	−0.0041 (8)	0.0041 (8)	−0.0044 (7)
CB_2	0.0198 (13)	0.0172 (11)	0.0196 (12)	−0.0051 (10)	0.0013 (10)	−0.0055 (9)
CG_2	0.0244 (14)	0.0215 (13)	0.0301 (15)	−0.0074 (11)	0.0077 (12)	−0.0095 (11)
CD1_2	0.045 (2)	0.0279 (16)	0.056 (2)	−0.0113 (15)	0.0239 (18)	0.0007 (15)
CD2_2	0.0258 (17)	0.064 (2)	0.050 (2)	−0.0154 (17)	0.0054 (16)	−0.0278 (19)
N_3	0.0147 (10)	0.0153 (9)	0.0170 (10)	−0.0015 (8)	0.0034 (8)	−0.0026 (8)
CA_3	0.0126 (11)	0.0193 (12)	0.0192 (12)	−0.0002 (9)	−0.0018 (10)	−0.0056 (10)
C_3	0.0158 (12)	0.0171 (11)	0.0153 (11)	0.0014 (9)	−0.0041 (9)	−0.0012 (9)
O_3	0.0175 (9)	0.0380 (12)	0.0236 (10)	0.0063 (9)	−0.0021 (8)	−0.0136 (9)
CB_3	0.0303 (15)	0.0301 (14)	0.0231 (13)	0.0125 (13)	−0.0098 (12)	−0.0048 (12)
CG_3	0.0193 (17)	0.025 (2)	0.0189 (16)	0.0022 (15)	−0.0027 (13)	−0.0051 (17)
OD1_3	0.0300 (15)	0.050 (2)	0.0222 (14)	−0.0128 (14)	−0.0109 (12)	0.0114 (12)
OD2_3	0.0325 (16)	0.0277 (15)	0.0464 (19)	−0.0051 (13)	−0.0206 (14)	−0.0004 (13)
N_4	0.0144 (10)	0.0160 (9)	0.0117 (9)	−0.0018 (8)	−0.0028 (8)	−0.0022 (8)
CA_4	0.0140 (11)	0.0133 (10)	0.0122 (10)	−0.0018 (9)	−0.0009 (9)	−0.0032 (8)
C_4	0.0092 (10)	0.0201 (12)	0.0147 (11)	−0.0030 (9)	0.0000 (9)	−0.0025 (9)
O_4	0.0184 (9)	0.0238 (9)	0.0152 (8)	−0.0018 (8)	0.0024 (7)	−0.0063 (7)
CB_4	0.0128 (11)	0.0195 (11)	0.0115 (10)	−0.0027 (9)	−0.0026 (9)	−0.0028 (9)
OG1_4	0.0147 (8)	0.0208 (9)	0.0155 (8)	0.0012 (7)	−0.0043 (7)	−0.0051 (7)
CG2_4	0.0197 (13)	0.0247 (13)	0.0198 (12)	−0.0070 (11)	−0.0001 (10)	0.0029 (10)
N_5	0.0139 (10)	0.0185 (10)	0.0126 (9)	−0.0010 (8)	0.0021 (8)	−0.0001 (8)
CA_5	0.0130 (11)	0.0187 (11)	0.0134 (10)	−0.0019 (9)	0.0010 (9)	0.0019 (9)
C_5	0.0133 (11)	0.0172 (11)	0.0155 (11)	−0.0027 (9)	−0.0002 (9)	0.0012 (9)
O_5	0.0176 (9)	0.0302 (10)	0.0121 (8)	−0.0004 (8)	−0.0001 (7)	0.0024 (7)
CB_5	0.0206 (13)	0.0179 (12)	0.0202 (12)	0.0015 (10)	0.0015 (11)	0.0010 (10)
CG_5	0.0236 (14)	0.0215 (13)	0.0239 (13)	−0.0041 (11)	−0.0011 (11)	0.0051 (11)
CD1_5	0.046 (2)	0.0318 (16)	0.0345 (17)	−0.0088 (15)	−0.0150 (16)	0.0138 (14)
CD2_5	0.047 (2)	0.0223 (14)	0.0354 (17)	−0.0093 (14)	−0.0002 (16)	0.0034 (12)
N_6	0.0129 (10)	0.0236 (11)	0.0114 (9)	−0.0033 (8)	0.0003 (8)	−0.0006 (8)
CA_6	0.0104 (11)	0.0223 (12)	0.0168 (11)	−0.0007 (9)	0.0001 (9)	0.0003 (9)
C_6	0.0137 (11)	0.0282 (13)	0.0127 (11)	0.0001 (10)	−0.0034 (9)	−0.0006 (10)
O_6	0.0119 (9)	0.0403 (12)	0.0262 (10)	−0.0016 (9)	0.0024 (8)	−0.0076 (9)
CB_6	0.0130 (11)	0.0244 (13)	0.0192 (12)	−0.0047 (10)	−0.0035 (10)	0.0013 (10)
CG_6	0.0190 (13)	0.0276 (14)	0.0207 (13)	−0.0032 (11)	−0.0036 (11)	−0.0049 (11)
CD1_6	0.054 (2)	0.0232 (15)	0.0410 (19)	−0.0055 (15)	0.0105 (17)	−0.0040 (14)
CD2_6	0.049 (2)	0.0407 (19)	0.054 (2)	0.0003 (18)	−0.033 (2)	−0.0162 (17)
N_7	0.0139 (10)	0.0250 (11)	0.0154 (10)	−0.0001 (9)	0.0009 (8)	−0.0025 (9)
CA_7	0.0177 (12)	0.0220 (12)	0.0200 (12)	0.0038 (10)	0.0002 (10)	−0.0009 (10)
C_7	0.0129 (11)	0.0274 (13)	0.0178 (12)	0.0002 (10)	−0.0004 (10)	−0.0030 (10)
O_7	0.0295 (11)	0.0299 (10)	0.0255 (10)	0.0058 (9)	0.0028 (9)	−0.0083 (9)
CB_7	0.0257 (14)	0.0199 (13)	0.0265 (14)	−0.0001 (11)	−0.0009 (12)	−0.0001 (11)
OG_7	0.0183 (10)	0.0264 (10)	0.0231 (10)	−0.0021 (8)	0.0015 (8)	−0.0074 (8)
N_8	0.0165 (10)	0.0254 (11)	0.0135 (10)	0.0000 (9)	−0.0028 (8)	−0.0014 (9)
CA_8	0.0120 (11)	0.0338 (14)	0.0156 (12)	−0.0033 (11)	0.0006 (9)	0.0015 (10)
C_8	0.0197 (13)	0.0413 (16)	0.0136 (11)	−0.0084 (12)	−0.0011 (11)	0.0037 (11)
O_8	0.0401 (14)	0.092 (2)	0.0134 (9)	−0.0378 (15)	−0.0006 (10)	0.0046 (12)
CB_8	0.0228 (14)	0.0343 (15)	0.0230 (13)	0.0022 (12)	0.0030 (11)	0.0078 (12)
CG_8	0.047 (2)	0.0305 (16)	0.0287 (16)	−0.0047 (15)	−0.0043 (15)	−0.0043 (13)
CD1_8	0.071 (4)	0.031 (2)	0.182 (8)	0.001 (2)	0.007 (5)	−0.018 (3)
CD2_8	0.0319 (19)	0.046 (2)	0.081 (3)	−0.0172 (17)	−0.002 (2)	−0.013 (2)
N_9	0.0145 (10)	0.0273 (11)	0.0125 (9)	−0.0044 (9)	−0.0015 (8)	−0.0026 (8)
CA_9	0.0158 (12)	0.0243 (12)	0.0131 (10)	−0.0032 (10)	−0.0004 (9)	−0.0027 (10)
C_9	0.0177 (12)	0.0285 (13)	0.0116 (11)	−0.0039 (11)	−0.0002 (9)	0.0012 (10)
O_9	0.0258 (11)	0.0319 (11)	0.0202 (9)	−0.0039 (9)	−0.0085 (8)	−0.0038 (8)
CB_9	0.0225 (14)	0.0253 (13)	0.0161 (12)	−0.0029 (11)	0.0009 (10)	−0.0021 (10)
CG_9	0.0335 (16)	0.0281 (14)	0.0176 (12)	0.0035 (13)	−0.0051 (12)	−0.0060 (11)
CD_9	0.0316 (16)	0.0313 (14)	0.0228 (14)	0.0037 (13)	−0.0070 (12)	−0.0100 (12)
OE1_9	0.0348 (12)	0.0437 (13)	0.0287 (11)	0.0124 (11)	−0.0124 (10)	−0.0171 (10)
NE2_9	0.0425 (17)	0.0544 (19)	0.0332 (15)	0.0207 (16)	−0.0167 (14)	−0.0248 (14)
N_10	0.0196 (11)	0.0298 (12)	0.0184 (10)	0.0023 (10)	−0.0071 (9)	−0.0045 (9)
CA_10	0.0244 (14)	0.0291 (14)	0.0205 (13)	0.0028 (12)	−0.0093 (11)	−0.0008 (11)
C_10	0.0190 (13)	0.0249 (13)	0.0300 (14)	−0.0004 (11)	−0.0078 (12)	0.0027 (11)
O_10	0.0317 (13)	0.0407 (14)	0.0723 (19)	−0.0148 (12)	0.0094 (13)	−0.0129 (14)
CB_10	0.0280 (15)	0.0353 (16)	0.0242 (14)	−0.0015 (13)	0.0007 (12)	0.0040 (12)
CG_10	0.043 (2)	0.0404 (18)	0.0384 (18)	0.0057 (16)	−0.0016 (16)	0.0117 (15)
CD1_10	0.064 (3)	0.063 (3)	0.067 (3)	−0.004 (3)	−0.013 (3)	0.037 (2)
CD2_10	0.053 (2)	0.058 (2)	0.0404 (19)	0.017 (2)	−0.0142 (19)	0.0049 (18)
N_11	0.0260 (12)	0.0290 (12)	0.0216 (11)	−0.0090 (10)	0.0003 (10)	0.0018 (10)
CA_11	0.0182 (13)	0.0353 (16)	0.0256 (14)	−0.0066 (12)	−0.0001 (11)	0.0050 (12)
C_11	0.0163 (13)	0.0410 (17)	0.0210 (13)	−0.0042 (12)	−0.0039 (11)	0.0034 (12)
O_11	0.0138 (10)	0.0700 (18)	0.0464 (15)	−0.0096 (11)	−0.0025 (10)	0.0236 (13)
CB_11	0.0289 (16)	0.0377 (17)	0.0286 (15)	−0.0091 (14)	0.0048 (13)	−0.0052 (13)
CG1_11	0.042 (2)	0.0323 (17)	0.071 (3)	−0.0019 (17)	−0.003 (2)	−0.0078 (18)
CG2_11	0.071 (3)	0.051 (2)	0.041 (2)	−0.021 (2)	0.023 (2)	−0.0145 (18)
CD_11	0.073 (3)	0.039 (2)	0.088 (4)	−0.005 (2)	−0.006 (3)	−0.011 (2)
N_12	0.0099 (9)	0.0313 (12)	0.0170 (10)	0.0010 (9)	−0.0009 (8)	0.0006 (9)
CA_12	0.0141 (11)	0.0296 (13)	0.0129 (11)	0.0004 (10)	−0.0019 (9)	−0.0032 (10)
C_12	0.0127 (11)	0.0311 (14)	0.0150 (11)	0.0026 (11)	−0.0004 (9)	−0.0020 (10)
O_12	0.0433 (14)	0.0579 (16)	0.0254 (11)	0.0330 (13)	−0.0133 (10)	−0.0182 (11)
CB_12	0.0176 (12)	0.0265 (13)	0.0170 (12)	0.0020 (11)	−0.0016 (10)	−0.0020 (10)
CG_12	0.0206 (13)	0.0212 (12)	0.0172 (12)	0.0056 (10)	−0.0015 (10)	−0.0010 (10)
OD1_12	0.0273 (11)	0.0375 (12)	0.0260 (10)	−0.0059 (10)	0.0020 (9)	−0.0119 (9)
OD2_12	0.0330 (12)	0.0321 (11)	0.0194 (9)	−0.0030 (9)	0.0025 (9)	−0.0081 (8)
O_13	0.0211 (11)	0.0638 (16)	0.0243 (10)	−0.0131 (11)	0.0037 (9)	−0.0124 (11)
O_14	0.0219 (12)	0.110 (3)	0.0203 (11)	−0.0196 (14)	−0.0024 (9)	0.0068 (13)
O_15	0.077 (2)	0.0705 (19)	0.0267 (12)	−0.0274 (19)	0.0162 (14)	−0.0075 (13)
O_16	0.040 (2)	0.059 (2)	0.0401 (19)	−0.0121 (18)	0.0126 (16)	−0.0064 (17)

Geometric parameters (Å, º)

O_1—C_1	1.237 (3)	C_6—N_7	1.338 (4)
C_1—N_2	1.346 (4)	CB_6—CG_6	1.542 (4)
C_1—C1_1	1.509 (4)	CG_6—CD1_6	1.525 (4)
C1_1—C2_1	1.526 (4)	CG_6—CD2_6	1.527 (4)
C2_1—O2_1	1.441 (4)	N_7—CA_7	1.455 (4)
C2_1—C3_1	1.522 (4)	CA_7—C_7	1.526 (4)
C3_1—C4_1	1.527 (4)	CA_7—CB_7	1.530 (4)
C4_1—C5_1	1.532 (4)	C_7—O_7	1.233 (3)
C5_1—C6_1	1.524 (4)	C_7—N_8	1.342 (4)
C6_1—C7_1	1.519 (4)	CB_7—OG_7	1.426 (4)
C7_1—C8_1	1.521 (4)	N_8—CA_8	1.454 (3)
C8_1—C9_1	1.522 (5)	CA_8—C_8	1.516 (4)
N_2—CA_2	1.467 (3)	CA_8—CB_8	1.536 (4)
CA_2—C_2	1.518 (4)	C_8—O_8	1.235 (4)
CA_2—CB_2	1.531 (4)	C_8—N_9	1.343 (4)
C_2—O_2	1.230 (3)	CB_8—CG_8	1.531 (5)
C_2—N_3	1.350 (3)	CG_8—CD2_8	1.495 (6)
CB_2—CG_2	1.536 (4)	CG_8—CD1_8	1.526 (6)
CG_2—CD2_2	1.505 (5)	N_9—CA_9	1.465 (3)
CG_2—CD1_2	1.538 (5)	CA_9—C_9	1.522 (4)
N_3—CA_3	1.452 (3)	CA_9—CB_9	1.531 (4)
CA_3—CB_3	1.504 (4)	C_9—O_9	1.246 (3)
CA_3—C_3	1.532 (3)	C_9—N_10	1.327 (4)
C_3—O_3	1.227 (3)	CB_9—CG_9	1.518 (4)
C_3—N_4	1.354 (3)	CG_9—CD_9	1.515 (4)
CB_3—CGA_3	1.387 (15)	CD_9—OE1_9	1.254 (4)
CB_3—CG_3	1.561 (5)	CD_9—NE2_9	1.314 (5)
CG_3—OD2_3	1.195 (5)	N_10—CA_10	1.467 (4)
CG_3—OD1_3	1.317 (5)	CA_10—CB_10	1.522 (4)
CGA_3—OD1A_3	1.21 (2)	CA_10—C_10	1.532 (4)
CGA_3—OD2A_3	1.29 (2)	C_10—O_10	1.219 (4)
N_4—CA_4	1.449 (3)	C_10—N_11	1.343 (4)
CA_4—CB_4	1.532 (4)	CB_10—CG_10	1.534 (5)
CA_4—C_4	1.545 (3)	CG_10—CD2_10	1.514 (6)
C_4—O_4	1.235 (3)	CG_10—CD1_10	1.520 (6)
C_4—N_5	1.331 (3)	N_11—CA_11	1.460 (4)
CB_4—OG1_4	1.452 (3)	CA_11—C_11	1.527 (4)
CB_4—CG2_4	1.510 (4)	CA_11—CB_11	1.541 (5)
OG1_4—C_12	1.343 (3)	C_11—O_11	1.234 (4)
N_5—CA_5	1.466 (3)	C_11—N_12	1.334 (4)
CA_5—C_5	1.535 (4)	CB_11—CG2_11	1.525 (5)
CA_5—CB_5	1.542 (4)	CB_11—CG1_11	1.529 (6)
C_5—O_5	1.240 (3)	CG1_11—CD_11	1.541 (6)
C_5—N_6	1.346 (3)	N_12—CA_12	1.455 (4)
CB_5—CG_5	1.519 (4)	CA_12—C_12	1.526 (3)
CG_5—CD1_5	1.531 (4)	CA_12—CB_12	1.529 (4)
CG_5—CD2_5	1.532 (4)	C_12—O_12	1.197 (4)
N_6—CA_6	1.458 (3)	CB_12—CG_12	1.515 (4)
CA_6—CB_6	1.532 (4)	CG_12—OD2_12	1.214 (4)
CA_6—C_6	1.532 (4)	CG_12—OD1_12	1.313 (4)
C_6—O_6	1.233 (3)
O_1—C_1—N_2	121.4 (2)	CA_6—CB_6—CG_6	115.8 (2)
O_1—C_1—C1_1	121.0 (2)	CD1_6—CG_6—CD2_6	111.0 (3)
N_2—C_1—C1_1	117.5 (2)	CD1_6—CG_6—CB_6	113.3 (2)
C_1—C1_1—C2_1	109.2 (2)	CD2_6—CG_6—CB_6	108.7 (3)
O2_1—C2_1—C3_1	111.4 (2)	C_6—N_7—CA_7	121.1 (2)
O2_1—C2_1—C1_1	109.2 (2)	N_7—CA_7—C_7	113.4 (2)
C3_1—C2_1—C1_1	112.6 (2)	N_7—CA_7—CB_7	110.8 (2)
C2_1—C3_1—C4_1	112.7 (2)	C_7—CA_7—CB_7	107.0 (2)
C3_1—C4_1—C5_1	113.4 (3)	O_7—C_7—N_8	123.3 (3)
C6_1—C5_1—C4_1	113.5 (2)	O_7—C_7—CA_7	119.1 (3)
C7_1—C6_1—C5_1	113.3 (2)	N_8—C_7—CA_7	117.5 (2)
C6_1—C7_1—C8_1	113.7 (3)	OG_7—CB_7—CA_7	112.5 (2)
C7_1—C8_1—C9_1	112.9 (3)	C_7—N_8—CA_8	120.8 (2)
C_1—N_2—CA_2	120.3 (2)	N_8—CA_8—C_8	112.9 (2)
N_2—CA_2—C_2	112.0 (2)	N_8—CA_8—CB_8	110.4 (2)
N_2—CA_2—CB_2	110.6 (2)	C_8—CA_8—CB_8	109.9 (2)
C_2—CA_2—CB_2	108.8 (2)	O_8—C_8—N_9	121.1 (3)
O_2—C_2—N_3	121.8 (2)	O_8—C_8—CA_8	119.2 (3)
O_2—C_2—CA_2	121.1 (2)	N_9—C_8—CA_8	119.7 (2)
N_3—C_2—CA_2	116.9 (2)	CG_8—CB_8—CA_8	115.0 (3)
CA_2—CB_2—CG_2	113.7 (2)	CD2_8—CG_8—CD1_8	109.3 (4)
CD2_2—CG_2—CB_2	110.7 (3)	CD2_8—CG_8—CB_8	112.1 (3)
CD2_2—CG_2—CD1_2	111.3 (3)	CD1_8—CG_8—CB_8	108.8 (4)
CB_2—CG_2—CD1_2	111.3 (3)	C_8—N_9—CA_9	120.2 (2)
C_2—N_3—CA_3	116.8 (2)	N_9—CA_9—C_9	113.9 (2)
N_3—CA_3—CB_3	111.4 (2)	N_9—CA_9—CB_9	111.1 (2)
N_3—CA_3—C_3	112.1 (2)	C_9—CA_9—CB_9	109.3 (2)
CB_3—CA_3—C_3	112.7 (2)	O_9—C_9—N_10	123.3 (3)
O_3—C_3—N_4	122.9 (2)	O_9—C_9—CA_9	118.5 (3)
O_3—C_3—CA_3	120.7 (2)	N_10—C_9—CA_9	118.2 (2)
N_4—C_3—CA_3	116.5 (2)	CG_9—CB_9—CA_9	112.6 (2)
CGA_3—CB_3—CA_3	139.1 (8)	CD_9—CG_9—CB_9	114.0 (2)
CGA_3—CB_3—CG_3	31.4 (7)	OE1_9—CD_9—NE2_9	122.8 (3)
CA_3—CB_3—CG_3	107.8 (3)	OE1_9—CD_9—CG_9	120.9 (3)
OD2_3—CG_3—OD1_3	124.2 (4)	NE2_9—CD_9—CG_9	116.3 (3)
OD2_3—CG_3—CB_3	125.4 (3)	C_9—N_10—CA_10	121.5 (2)
OD1_3—CG_3—CB_3	110.4 (3)	N_10—CA_10—CB_10	110.0 (3)
OD1A_3—CGA_3—OD2A_3	123.4 (15)	N_10—CA_10—C_10	107.4 (2)
OD1A_3—CGA_3—CB_3	129.1 (15)	CB_10—CA_10—C_10	119.1 (3)
OD2A_3—CGA_3—CB_3	106.8 (13)	O_10—C_10—N_11	121.5 (3)
C_3—N_4—CA_4	118.5 (2)	O_10—C_10—CA_10	120.8 (3)
N_4—CA_4—CB_4	109.3 (2)	N_11—C_10—CA_10	117.6 (3)
N_4—CA_4—C_4	111.3 (2)	CA_10—CB_10—CG_10	114.3 (3)
CB_4—CA_4—C_4	111.8 (2)	CD2_10—CG_10—CD1_10	108.9 (4)
O_4—C_4—N_5	122.2 (2)	CD2_10—CG_10—CB_10	112.9 (3)
O_4—C_4—CA_4	120.9 (2)	CD1_10—CG_10—CB_10	108.8 (3)
N_5—C_4—CA_4	116.9 (2)	C_10—N_11—CA_11	120.7 (3)
OG1_4—CB_4—CG2_4	108.8 (2)	N_11—CA_11—C_11	108.2 (3)
OG1_4—CB_4—CA_4	104.83 (19)	N_11—CA_11—CB_11	110.2 (2)
CG2_4—CB_4—CA_4	112.4 (2)	C_11—CA_11—CB_11	112.0 (3)
C_12—OG1_4—CB_4	117.7 (2)	O_11—C_11—N_12	121.5 (3)
C_4—N_5—CA_5	121.5 (2)	O_11—C_11—CA_11	121.1 (3)
N_5—CA_5—C_5	111.6 (2)	N_12—C_11—CA_11	117.3 (3)
N_5—CA_5—CB_5	107.1 (2)	CG2_11—CB_11—CG1_11	112.4 (4)
C_5—CA_5—CB_5	111.3 (2)	CG2_11—CB_11—CA_11	110.7 (3)
O_5—C_5—N_6	122.4 (2)	CG1_11—CB_11—CA_11	109.2 (3)
O_5—C_5—CA_5	121.0 (2)	CB_11—CG1_11—CD_11	114.8 (4)
N_6—C_5—CA_5	116.6 (2)	C_11—N_12—CA_12	119.4 (2)
CG_5—CB_5—CA_5	116.3 (2)	N_12—CA_12—C_12	110.1 (2)
CB_5—CG_5—CD1_5	112.0 (2)	N_12—CA_12—CB_12	110.5 (2)
CB_5—CG_5—CD2_5	108.6 (2)	C_12—CA_12—CB_12	111.3 (2)
CD1_5—CG_5—CD2_5	111.2 (3)	O_12—C_12—OG1_4	125.3 (3)
C_5—N_6—CA_6	121.6 (2)	O_12—C_12—CA_12	125.9 (3)
N_6—CA_6—CB_6	111.5 (2)	OG1_4—C_12—CA_12	108.8 (2)
N_6—CA_6—C_6	113.0 (2)	CG_12—CB_12—CA_12	111.1 (2)
CB_6—CA_6—C_6	109.2 (2)	OD2_12—CG_12—OD1_12	125.1 (3)
O_6—C_6—N_7	121.7 (3)	OD2_12—CG_12—CB_12	122.6 (3)
O_6—C_6—CA_6	119.9 (2)	OD1_12—CG_12—CB_12	112.3 (2)
N_7—C_6—CA_6	118.3 (2)