L-Valyl-L-serine trihydrate

The valine side chains in the crystal structure of the title compound [systematic name: 2-(2-ammonio-3-methyl­butan­amido)-3-hydroxy­propano­ate tri­hydrate], C₈H₁₆N₂O₄·3H₂O, stack along an a axis of 4.77 Å to form hydro­phobic columns surrounded by remarkable water/hydroxyl shells. The peptide main chains are connected by hydrogen bonds in two-dimensional layers. The peptide mol­ecules in each layer are related only by translation, and generate a very rare pattern. This is rendered possible through the formation of the shortest C^[alpha]-H...O(carboxyl­ate) inter­action ever recorded.

S1. Comment

As part of a systematic survey of dipeptides with one hydrophobic and one hydrophilic residue (Netland et al., 2004), the structure of L-valyl-L-serine trihydrate, (I), has been determined.

The asymmetric unit of (I), with one peptide molecule and three water molecules, is shown in Fig. 1. The peptide main chain is quite extended, as reflected by the torsion angles given in Table 1. The valine side chain has a common trans/gauche- orientation for N1—C1—C2—C3/N1—C1—C2—C4, while a search in the Cambridge Structural Database (CSD, Version 5.25, November 2003; Allen, 2002) shows that gauche+ for N2—C6—C7—O2 represents the most frequently observed serine conformation.

Fig. 2 illustrates the crystal packing pattern of (I). The peptide main chains generate layers, seen edge-on in Fig. 2, through hydrogen bonding. The most notable structural feature is the fact that the molecules in a layer are, in an unusual manner, lined up perpendicular to the unique axis, rather than along it, as one might expect. Consequently, all valine side chains point in the same direction. Under these circumstances, the hydrophobic groups cannot form separate layers, as they normally do in peptide crystals with a tight two-dimensional association of peptide main chains. Rather, the valine side chains are stacked into hydrophobic columns along the very short a axis [4.77 Å]; we find fewer than 20 other peptides with a shorter crystallographic axis in the CSD. Each column is surrounded by a hydrophilic shell of water molecules and serine hydroxyl groups in a quite unusual manner. Numerous C—H···O contacts are involved, including C4—H42···O3(x + 1, y, z + 1) (Fig. 2), with an H···O distance of 2.59 Å (Table 2). The rest of the contacts have H···O distances greater than 2.80 Å. The construction of a related water cage around a valine side chain was observed for L-phenylalanyl-L-valine (Görbitz, 2002), with comparable H···O and C···O distances.

Out of about 100 distinctly different dipeptide structures with a zwitterionic peptide main chain in the CSD, 37 contain hydrogen-bonded layers in which each amino group donates H atoms to two independent carboxylate groups which are related by a simple unit-cell translation, or in some cases with Z' > 1 by pseudotranslational symmetry. Consecutive molecules in the resulting head-to-tail chains (Suresh & Vijayan, 1985) are usually related by a twofold screw operation in space group P2₁ or P2₁2₁2₁. In (I), the layers generated by hydrogen bonding between the peptide main chains involve molecules related by translation only (Fig. 3), a phenomenon observed for only eight other dipeptide structures. Only the structure of L-glutamyl-L-aspartic acid hydrate, (II) (Eggleston & Hodgson, 1985), in space group P1, contains a fairly similar pattern (Fig. 3). The main differences between (I) and (II) concern a long N—H···O hydrogen bond in (II) (labelled 1 in Fig. 3; H···O 2.50 Å and N—H···O 143°) that has normal dimensions for this type of interaction in (I) (1.93 Å and 170°; Table 2), and a weak secondary interaction in (II) (2 in Fig. 3; 2.60 Å and 120°) that is missing in (I) (3.18 Å and 94°). A comparison of the main-chain conformations showns significant differences; the values for ψ₁, ω₁, ϕ₂ and ψ_T [N1—C1—C5—N2, C1—C5—N2—C6, C5—N2—C6—C8 and N2—C6—C8—O3 in (I)] are 148.0, 161.3, −118.2 and −31.9°, respectively, in (II), compared with 134.16 (7), 174.68 (7), −160.24 (8) and 0.38 (10)°, respectively, in (I) (Table 1).

The classic paper by Suresh & Vijayan (1985) on head-to-tail chains lists a series of theoretical layered aggregation patterns for dipeptides, but does not include the pattern illustrated in Fig. 3. The reason is probably that, at the time, the importance of C—H···O interactions had not yet been realised. As is evident from Fig. 3, C^α—H···O(carboxylate) interactions play a key role in completing the hydrogen-bond network of (I). Thus, the tapes with carbonyl acceptors, familiar from about 12 other dipeptide structures, have C₁^α—H as well as >N—H donors. More uncommon is the C₂^α—H···O(carboxylate) interaction (labelled 3 in Fig. 3). A total number of about 250 peptide structures in the CSD have an unprotected negatively charged C-terminal carboxylate group. Within this subset, there are 33 C^α—H···O(carboxylate) interactions (in 25 structures) with H···O distance < 2.60 Å, but only eight (in six structures) with H···O < 2.40 Å. In (I), H61···O3(x + 1, y, z) is 2.28 Å, the smallest value ever recorded for this type of contact. The corresponding distance in (II) is 2.51 Å.

Apart from the presence of two amino···carboxylate hydrogen bonds, there are few similarities between the structure of (I) and the structures of L-alanyl-L-serine (Jones et al., 1978) and the retroanalogue L-seryl-L-valine, studied previously as part of our ongoing investigation (Moen et al., 2004). This is not unexpected, since (I) was crystallized as a trihydrate, while the other two structures are devoid of solvent water moleules.

S2. Experimental

The title compound was obtained from Bachem. Crystals were grown by diffusion of acetonitrile into 30µl of an aqueous solution containing about 1 mg of the peptide.

S3. Refinement

Positional parameters were refined for H atoms bonded to N and O atoms. Other H atoms were positioned with idealized geometry and fixed C—H distances in the range 0.98–1.00 Å Please check added text. U_iso(H) values were 1.2U_eq of the carrier atom, or 1.5U_eq for amino and methyl groups and for water molecules. In the absence of significant anomalous scattering effects, 1916 Friedel pairs were merged. The absolute configuration was known for the purchased material.

Computing details

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Bruker, 2000); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. The molecular structure of (I). Displacement ellipsoids are shown at the 50% probability level and H atoms are shown as spheres of arbitrary size.
	Fig. 2. The molecular packing and unit cell of (I), viewed along the a axis. Hydrogen bonding is indicated by dashed lines.
	Fig. 3. The hydrogen bonding between the peptide main chains in the structures of (I) and (II). For a description of 1, 2 and 3, see text.

2-(2-ammonio-3-methylbutanamido)-3-hydroxypropanoate trihydrate

Crystal data

C8H16N2O4·3H2O	F(000) = 280
Mr = 258.28	Dx = 1.322 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 4.7695 (2) Å	Cell parameters from 6036 reflections
b = 16.1323 (5) Å	θ = 2.4–37.8°
c = 8.6789 (3) Å	µ = 0.12 mm^−1
β = 103.636 (1)°	T = 105 K
V = 648.96 (4) Å^3	Needle, colourless
Z = 2	0.90 × 0.30 × 0.05 mm

Data collection

Siemens SMART CCD area-detector diffractometer	3564 independent reflections
Radiation source: fine-focus sealed tube	3309 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.026
Detector resolution: 8.3 pixels mm^-1	θmax = 37.8°, θmin = 2.4°
Sets of exposures each taken over 0.3° ω rotation scans	h = −8→8
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	k = −23→27
Tmin = 0.738, Tmax = 0.994	l = −14→14
9845 measured reflections

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)] = 0.031	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.083	H atoms treated by a mixture of independent and constrained refinement
S = 1.07	w = 1/[σ^2(Fo^2) + (0.0542P)^2] where P = (Fo^2 + 2Fc^2)/3
3564 reflections	(Δ/σ)max < 0.001
189 parameters	Δρmax = 0.38 e Å^−3
1 restraint	Δρmin = −0.23 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. Data were collected by measuring two sets of exposures with the detector set at 2θ = 29° and three sets of exposures with the detector set at 2θ = 55°, crystal-to-detector distance 5.08 cm. Refinement of F² against ALL reflections.

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

	x	y	z	Uiso*/Ueq
O1	0.71552 (13)	0.19696 (5)	0.50129 (8)	0.01886 (12)
O2	0.04617 (17)	0.06576 (5)	0.20935 (9)	0.02353 (14)
H5	0.054 (4)	0.0645 (14)	0.305 (2)	0.035*
O3	−0.13086 (14)	0.27850 (5)	0.11828 (8)	0.01977 (13)
O4	0.06301 (14)	0.21670 (5)	−0.06325 (7)	0.01951 (12)
N1	0.49006 (15)	0.19819 (5)	0.77628 (8)	0.01454 (11)
H1	0.480 (4)	0.1508 (12)	0.7475 (18)	0.022*
H2	0.379 (4)	0.2004 (12)	0.8444 (19)	0.022*
H3	0.669 (4)	0.2072 (12)	0.8160 (19)	0.022*
N2	0.25663 (14)	0.22248 (5)	0.36224 (8)	0.01360 (11)
H4	0.098 (4)	0.2359 (10)	0.3655 (17)	0.016*
C1	0.38448 (16)	0.25649 (5)	0.64082 (8)	0.01250 (12)
H11	0.1698	0.2613	0.6202	0.015*
C2	0.52085 (19)	0.34294 (5)	0.67957 (10)	0.01736 (14)
H21	0.7350	0.3359	0.7123	0.021*
C3	0.4511 (4)	0.39910 (7)	0.53299 (14)	0.0361 (3)
H31	0.5295	0.4546	0.5618	0.054*
H32	0.2414	0.4026	0.4928	0.054*
H33	0.5378	0.3759	0.4507	0.054*
C4	0.4216 (2)	0.38332 (6)	0.81706 (12)	0.02363 (17)
H41	0.5333	0.4340	0.8497	0.035*
H42	0.4517	0.3447	0.9066	0.035*
H43	0.2163	0.3972	0.7830	0.035*
C5	0.46537 (15)	0.22119 (5)	0.49473 (9)	0.01278 (11)
C6	0.30036 (16)	0.19788 (5)	0.20816 (8)	0.01292 (12)
H61	0.4888	0.2209	0.1962	0.016*
C7	0.30820 (19)	0.10319 (5)	0.19349 (10)	0.01737 (14)
H71	0.3435	0.0884	0.0890	0.021*
H72	0.4701	0.0811	0.2764	0.021*
C8	0.05691 (16)	0.23510 (5)	0.07835 (9)	0.01386 (12)
O1W	−0.16044 (19)	0.44775 (5)	0.20405 (10)	0.02603 (15)
H11W	−0.156 (5)	0.3959 (15)	0.175 (3)	0.039*
H12W	−0.321 (5)	0.4627 (15)	0.162 (3)	0.039*
O2W	1.11366 (19)	0.06715 (5)	0.54931 (10)	0.02642 (15)
H21W	0.987 (5)	0.0947 (16)	0.552 (2)	0.040*
H22W	1.091 (5)	0.0294 (17)	0.606 (2)	0.040*
O3W	−0.30128 (18)	0.02436 (6)	−0.10050 (10)	0.02693 (15)
H31W	−0.180 (5)	−0.0002 (15)	−0.129 (2)	0.040*
H32W	−0.229 (4)	0.0332 (16)	0.015 (2)	0.040*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0116 (2)	0.0275 (3)	0.0168 (3)	0.0032 (2)	0.00218 (18)	−0.0014 (2)
O2	0.0271 (3)	0.0212 (3)	0.0214 (3)	−0.0076 (3)	0.0040 (2)	−0.0021 (2)
O3	0.0172 (3)	0.0222 (3)	0.0196 (3)	0.0060 (2)	0.0035 (2)	0.0023 (2)
O4	0.0167 (2)	0.0302 (3)	0.0107 (2)	0.0010 (2)	0.00156 (18)	0.0012 (2)
N1	0.0158 (3)	0.0157 (3)	0.0118 (2)	0.0011 (2)	0.0027 (2)	0.0005 (2)
N2	0.0110 (2)	0.0183 (3)	0.0106 (2)	0.0015 (2)	0.00077 (18)	−0.0013 (2)
C1	0.0116 (3)	0.0146 (3)	0.0106 (3)	0.0000 (2)	0.0011 (2)	−0.0006 (2)
C2	0.0190 (3)	0.0146 (3)	0.0174 (3)	−0.0026 (3)	0.0023 (2)	−0.0018 (3)
C3	0.0671 (9)	0.0176 (4)	0.0225 (5)	−0.0071 (5)	0.0082 (5)	0.0029 (3)
C4	0.0325 (5)	0.0171 (4)	0.0204 (4)	−0.0002 (3)	0.0045 (3)	−0.0055 (3)
C5	0.0117 (2)	0.0147 (3)	0.0113 (3)	−0.0007 (2)	0.00136 (19)	−0.0008 (2)
C6	0.0121 (3)	0.0158 (3)	0.0102 (3)	0.0002 (2)	0.0014 (2)	−0.0005 (2)
C7	0.0196 (3)	0.0160 (3)	0.0163 (3)	0.0025 (3)	0.0036 (3)	−0.0015 (3)
C8	0.0122 (3)	0.0165 (3)	0.0122 (3)	−0.0007 (2)	0.0015 (2)	0.0024 (2)
O1W	0.0246 (3)	0.0243 (3)	0.0270 (3)	0.0023 (3)	0.0016 (3)	−0.0054 (3)
O2W	0.0292 (4)	0.0216 (3)	0.0305 (4)	0.0039 (3)	0.0111 (3)	0.0077 (3)
O3W	0.0220 (3)	0.0285 (4)	0.0282 (4)	−0.0014 (3)	0.0019 (3)	−0.0010 (3)

Geometric parameters (Å, º)

O1—C5	1.2439 (9)	C3—H31	0.9800
O2—C7	1.4235 (11)	C3—H32	0.9800
O2—H5	0.82 (2)	C3—H33	0.9800
O3—C8	1.2486 (11)	C4—H41	0.9800
O4—C8	1.2712 (10)	C4—H42	0.9800
N1—C1	1.4970 (10)	C4—H43	0.9800
N1—H1	0.803 (19)	C6—C7	1.5340 (12)
N1—H2	0.883 (17)	C6—C8	1.5366 (11)
N1—H3	0.852 (17)	C6—H61	1.0000
N2—C5	1.3319 (10)	C7—H71	0.9900
N2—C6	1.4563 (10)	C7—H72	0.9900
N2—H4	0.794 (17)	O1W—H11W	0.88 (2)
C1—C5	1.5204 (11)	O1W—H12W	0.80 (2)
C1—C2	1.5420 (11)	O2W—H21W	0.76 (2)
C1—H11	1.0000	O2W—H22W	0.81 (3)
C2—C4	1.5292 (13)	O3W—H31W	0.79 (2)
C2—C3	1.5331 (14)	O3W—H32W	0.99 (2)
C2—H21	1.0000
C7—O2—H5	106.0 (15)	C2—C4—H41	109.5
C1—N1—H1	111.7 (12)	C2—C4—H42	109.5
C1—N1—H2	110.9 (12)	H41—C4—H42	109.5
H1—N1—H2	104.2 (17)	C2—C4—H43	109.5
C1—N1—H3	109.2 (12)	H41—C4—H43	109.5
H1—N1—H3	105.6 (18)	H42—C4—H43	109.5
H2—N1—H3	115.0 (15)	O1—C5—N2	123.93 (7)
C5—N2—C6	123.28 (6)	O1—C5—C1	120.58 (7)
C5—N2—H4	119.9 (10)	N2—C5—C1	115.41 (6)
C6—N2—H4	116.8 (11)	N2—C6—C7	111.05 (7)
N1—C1—C5	108.37 (6)	N2—C6—C8	108.64 (6)
N1—C1—C2	110.51 (6)	C7—C6—C8	110.93 (7)
C5—C1—C2	110.11 (6)	N2—C6—H61	108.7
N1—C1—H11	109.3	C7—C6—H61	108.7
C5—C1—H11	109.3	C8—C6—H61	108.7
C2—C1—H11	109.3	O2—C7—C6	112.04 (7)
C4—C2—C3	110.44 (9)	O2—C7—H71	109.2
C4—C2—C1	111.30 (7)	C6—C7—H71	109.2
C3—C2—C1	110.83 (8)	O2—C7—H72	109.2
C4—C2—H21	108.0	C6—C7—H72	109.2
C3—C2—H21	108.0	H71—C7—H72	107.9
C1—C2—H21	108.0	O3—C8—O4	125.50 (8)
C2—C3—H31	109.5	O3—C8—C6	118.89 (7)
C2—C3—H32	109.5	O4—C8—C6	115.60 (7)
H31—C3—H32	109.5	H11W—O1W—H12W	104 (2)
C2—C3—H33	109.5	H21W—O2W—H22W	102 (2)
H31—C3—H33	109.5	H31W—O3W—H32W	106.7 (19)
H32—C3—H33	109.5
N1—C1—C5—N2	134.16 (7)	C6—N2—C5—O1	−1.94 (13)
C1—C5—N2—C6	174.68 (7)	N1—C1—C5—O1	−49.10 (10)
C5—N2—C6—C8	−160.24 (8)	C2—C1—C5—O1	71.88 (10)
N2—C6—C8—O3	0.38 (10)	C2—C1—C5—N2	−104.87 (8)
N1—C1—C2—C3	171.31 (9)	C5—N2—C6—C7	77.50 (9)
N1—C1—C2—C4	−65.36 (9)	C8—C6—C7—O2	−60.50 (9)
N2—C6—C7—O2	60.42 (9)	C7—C6—C8—O3	122.72 (8)
C6—C7—O2—H5	−79.3 (16)	N2—C6—C8—O4	−178.13 (7)
C5—C1—C2—C4	174.95 (7)	C7—C6—C8—O4	−55.79 (10)
C5—C1—C2—C3	51.63 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2W^i	0.803 (19)	2.533 (18)	3.1472 (12)	134.4 (16)
N1—H1···O3W^ii	0.803 (19)	2.518 (18)	3.0816 (12)	128.4 (14)
N1—H2···O4^iii	0.883 (17)	1.885 (17)	2.7413 (10)	163.1 (16)
N1—H3···O4^ii	0.852 (17)	1.932 (17)	2.7752 (9)	170.1 (17)
N2—H4···O1^i	0.794 (17)	2.475 (16)	3.1233 (9)	139.7 (15)
O2—H5···O2W^i	0.82 (2)	2.07 (2)	2.8917 (12)	174 (2)
C1—H11···O1^i	1.00	2.41	3.2783 (10)	146
C4—H42···O3^ii	0.98	2.59	3.4086 (12)	140
C6—H61···O3^iv	1.00	2.28	3.2645 (11)	169
O1W—H11W···O3	0.88 (2)	1.97 (2)	2.8423 (11)	177 (2)
O1W—H12W···O3W^v	0.80 (2)	2.02 (2)	2.7997 (12)	165 (2)
O2W—H21W···O1	0.76 (2)	2.08 (3)	2.7915 (11)	157 (2)
O2W—H22W···O1W^vi	0.81 (3)	2.07 (2)	2.8490 (11)	161 (2)
O3W—H31W···O1W^vii	0.79 (2)	2.06 (2)	2.8492 (13)	174 (2)
O3W—H32W···O2	0.99 (2)	1.95 (2)	2.8849 (11)	156.6 (18)

Symmetry codes: (i) x−1, y, z; (ii) x+1, y, z+1; (iii) x, y, z+1; (iv) x+1, y, z; (v) −x−1, y+1/2, −z; (vi) −x+1, y−1/2, −z+1; (vii) −x, y−1/2, −z.