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Contribution of Weak S−H···O Hydrogen Bonds to the Side Chain Motions in D,L-Homocysteine on Cooling Vasily S. Minkov*,†,‡ and Elena V. Boldyreva*,†,‡ †

Novosibirsk State University, 2 Pirogov str., 630090 Novosibirsk, Russian Federation Institute of Solid State Chemistry and Mechanochemistry Siberian Branch of Russian Academy of Sciences, 18 Kutateladze str., 630128 Novosibirsk, Russian Federation

‡

S Supporting Information *

ABSTRACT: Sulfhydryl groups play an important role in the formation of native structures of proteins and their biological functions. In the present work, we report for the first time the crystal structure of D,L-homocysteine and the results of a detailed study of the dynamics of its sulfhydryl group on cooling by precise single-crystal X-ray diffraction combined with polarized Raman spectroscopy of oriented single crystals. Although the crystal structures of both D,L-cysteine and D,L-homocysteine are layered, hydrogen bonds formed by −SH groups differ. In contrast with the crystal structure of D,L-cysteine with weak S−H···S hydrogen bonds between layers, D,L-homocysteine resembles the structures of amino acids with hydrophobic aliphatic side chains with no hydrogen bonds between the layers. The side chain of D,L-homocysteine forms a three-centered S−H···O hydrogen bond with carboxylate groups of two neighboring zwitterions. On cooling down, despite the shortening of the two S···O distances in the bifurcated S−H···O hydrogen bond, the wavenumber of the stretching vibrations of −SH groups increases. The same effect was also observed previously for other sulfhydryl containing amino acids, L-cysteine, and N-acetyl-L-cysteine on increasing pressure and is related to the strengthening of a three-centered bifurcated S−H···O hydrogen bond.

1. INTRODUCTION Sufhydryl group of cysteine residue participates in numerous biological functions and biochemical processes1−4 and plays a vital role in specific interactions stabilizing the spatial structure of proteins.5−7 The ability of sulfhydryl group to be oxidized easily, along with proton migration, makes cysteine residue very important in numerous enzymes playing an important role in the red-ox homeostasis of cells.8−10 Its high affinity to bind with metals gives rise to metalloproteins such as zinc fingers and iron−sulfur proteins.11−14 Hydrogen bonds formed by sulfhydryl group are of special interest. Although S−H···X hydrogen bonds are known for a long time15 starting from early investigations of interactions in liquid mercaptans,16−19 they are still considered as nonclassical H bonds. However, S−H···X hydrogen bonds are not so weak as was previously believed. Spectroscopic studies of S−H···X hydrogen bonds have shown a large red shift of stretching vibrations of sulfhydryl group in a number of compounds (for example, in dithiotropolone,20 trithiocarbonic acid,21 phosphinodithioic acids22), indicating that such interactions can be strong. A structural study of S−H···X hydrogen bonds in proteins is complicated by poor quantity and quality of the data available on the crystal structures. The first works on the analysis of sulfur-containing hydrogen bonds in protein structures were published in the 1990s. They were based on the analysis of short contacts between terminal sulfhydryl group of cysteine residues and potential acceptors and revealed the possibility of the formation of these bonds.6,23,24 In a recent work,25 the © XXXX American Chemical Society

authors carried out a systematic analysis of numerous protein crystal structures known up to the time of publication and suggested more accurate values for the geometric parameters of S−H···X hydrogen bonds with different acceptors. Mean geometric parameters of S−H···O hydrogen bonds in proteins (H···O and S···O distances of 2.41 and 3.48 Å and S−H···O angle of 142.7°) are in a good agreement with those found in molecular crystals of compounds containing sulfhydryl groups.26 A molecular dynamics simulation has also shown that a hydrogen bond formed by a cysteine residue and a carbonyl O atom in the main backbone is quite stable.27 Moreover, using the cysteine markers that can be put at almost any position in a protein by standard methods of site-directed mutagenesis, one can follow the changes in hydrogen bonding and in the conformation of the side chain during functional processes in proteins in the hydrophobic core28 as well as at the active sites.29 Very important information about the energies of conformations of cysteine residues can be derived from ab initio studies of small molecules. Previous works showed the existence of many different conformers of a neutral cysteine molecule in the gas phase, most of them differing in energies within a 20 kJ mol−1 range.30−36 Some of the conformers were experimentally observed as neutral molecules by IR matrix Received: March 30, 2014 Revised: June 19, 2014

A

dx.doi.org/10.1021/jp503154x | J. Phys. Chem. B XXXX, XXX, XXX−XXX

B

275 5.1915(6) 5.5032(6) 11.4110(13) 102.745(9) 91.059(9) 107.105(9) 302.70(6) 1.483 0.442 3845 1629 1352 1.84 29.15 −7 → 7 −7 → 7 −15 → 14 0.0338 0.0380 0.0963 1.072 100 0.340 −0.409

295 5.1951(6) 5.5041(6) 11.4271(13) 102.665(8) 90.998(9) 107.131(9) 303.48(6) 1.480 0.440 3854 1633 1339 1.83 29.13

−7 → 7 −7 → 7 −15 → 14 0.0346 0.0382 0.1015 1.077 100 0.294 −0.442

−7 → 7 −7 → 7 −15 → 14 0.0359 0.0378 0.0979 1.089 100 0.347 −0.416

255 5.1897(6) 5.5033(6) 11.3966(13) 102.817(9) 91.102(9) 107.100(9) 302.10(6) 1.486 0.442 3834 1625 1378 1.84 29.14 −7 → 7 −7 → 7 −15 → 14 0.0359 0.0369 0.0961 1.104 100 0.373 −0.450

235 5.1850(6) 5.5008(6) 11.3777(12) 102.875(8) 91.152(9) 107.075(8) 301.13(6) 1.491 0.444 3826 1622 1383 1.84 29.16 −7 → 7 −7 → 7 −15 → 14 0.0354 0.0369 0.0976 1.057 100 0.379 −0.433

215 5.1838(6) 5.5014(6) 11.3669(12) 102.934(8) 91.190(9) 107.073(8) 300.71(6) 1.493 0.444 3821 1619 1395 1.85 29.16 −7 → 7 −7 → 7 −15 → 14 0.0369 0.0347 0.0915 1.066 100 0.353 −0.489

195 5.1788(5) 5.4990(5) 11.3501(11) 102.992(8) 91.237(8) 107.058(8) 299.77(5) 1.498 0.446 3809 1612 1415 1.85 29.13 −7 → 7 −7 → 7 −15 → 14 0.0371 0.0345 0.0905 1.066 100 0.369 −0.480

175 5.1785(5) 5.5003(5) 11.3433(11) 103.032(8) 91.273(8) 107.054(8) 299.58(5) 1.499 0.446 3808 1612 1420 1.85 29.14 −7 → 7 −7 → 7 −15 → 14 0.0406 0.0338 0.0898 1.081 100 0.408 −0.442

155 5.1741(5) 5.4977(5) 11.3292(11) 103.079(8) 91.286(8) 107.046(8) 298.75(5) 1.503 0.447 3806 1606 1428 1.85 29.09 −7 → 7 −7 → 7 −15 → 14 0.0432 0.0342 0.0906 1.052 100 0.321 −0.471

135 5.1725(5) 5.4987(5) 11.3229(11) 103.123(8) 91.313(8) 107.030(8) 298.50(5) 1.504 0.448 3804 1606 1430 1.86 29.10 −7 → 7 −7 → 7 −15 → 14 0.0333 0.0317 0.0821 1.111 100 0.401 −0.456

120 5.1707(5) 5.4969(5) 11.3141(11) 103.133(8) 91.352(8) 107.033(8) 298.02(5) 1.506 0.448 3803 1606 1456 1.86 29.12

−7 → 7 −7 → 7 −15 → 14 0.0387 0.0304 0.0795 1.090 100 0.422 −0.390

100 5.1682(5) 5.4961(5) 11.3055(11) 103.162(8) 91.377(8) 107.022(8) 297.58(5) 1.507 0.449 3790 1602 1465 1.86 29.12

a

For all structures: chemical formula, C4H9NO2S; Mr = 135.18 g mol−1; crystal size, 0.10 × 0.41 × 0.66 mm3; triclinic space group, P-1, Z = 2, Z′ = 1. Experiments were carried out with Mo-Kα radiation using a Stoe IPDS-II diffractometer. H atoms were found from difference Fourier maps and refined freely.

T/K a/Å b/Å c/Å α (deg) β (deg) γ (deg) V/Å3 Dcalc/g cm−3 μ/mm−1 no. of measured, independent, and observed [I > 2σ(I)] reflections θmin (deg) θmax (deg) range of h k l Rint R[F2 > 2σ(F2)] wR(F2) S no. of parameters Δρmax/e Å−3 Δρmin/e Å−3

Table 1. Crystal Data, Data Collection, and Structure Refinement Parameters for Crystal Structures of D,L-Homocysteine at Different Temperaturesa

The Journal of Physical Chemistry B Article


The Journal of Physical Chemistry B

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isolation spectroscopy37 and by laser ablation molecular beam Fourier-transform microwave spectroscopy38 as well as in zwitterionic state,33−35,39 although some zwitterions were characterized by the presence of thiolate and ammonium groups.32,39,40 The formation of different types of both “normal” and “unconventional” cysteine zwitterions was experimentally confirmed by extensive studies using different spectroscopic techniques on cysteine films adsorbed from gas phase or from solutions on a variety of surfaces, mostly on metals.41−45 However, adsorption of L-cysteine predominantly proceeds through dissociative interaction between the molecular sulfhydryl group and metal surfaces, that is, formation of thiolate and covalent Me-S bond. Such investigations provide significant information for better understanding of the folding and functioning processes in metalloproteins. Essential information about S−H···X hydrogen bonds can be derived from a study of molecular crystals of small amino acids and peptides. Combining precise diffraction data with a detailed analysis of vibrational characteristics of selected bonds participating in the formation of hydrogen bonds in the crystals of model systems is a powerful method of investigating specific interactions.46 Even a small amino acid, cysteine, shows different conformations of the side chain, and its side chain can be involved into different interactions. The −CH2−SH fragment in the crystals can adopt three main different conformations: gauche−, gauche+, and trans. They are characterized by the value of N−C−C−S torsion angle, which can be ca. −60, +60, and 180°, respectively.47 In the crystals of L- and D,L-cysteine under ambient conditions, the sulfhydryl group can be involved in the formation of S−H···O or S−H···S hydrogen bonds.48−52 Co-crystallization of cysteine with oxalic or tartaric acids increases the number of acceptor O atoms and leads to the formation of preferably S−H···O hydrogen bonds.47,53−56 Varying temperature or pressure allows one to study the dynamics of selected intramolecular bonds and intermolecular hydrogen bonds as well as of the structure as a whole. Increasing hydrostatic pressure leads to a series of phase transitions in L- and D,L-cysteine manifesting themselves in the reorientation of the side chain and switching of the S−H···X hydrogen bonds to the stronger ones, mostly to S−H···O.57−60 Cooling the crystals of L- and D,L-cysteine also leads to phase transitions: in D,L-cysteine, the phase transition is accompanied by the fragmentation of a crystal and switching of S−H···S hydrogen bonds to S−H···O.61−64 This transition strongly depends on the rate of variation of temperature and the particle size.65 The low-temperature phase transition in the orthorhombic L-cysteine is characterized by ordering of sulfhydryl groups and preserving the S−H···S hydrogen bonds. (Under ambient conditions a part of sulfhydryl groups forms S−H···O hydrogen bonds, whereas another part forms S−H···S bonds.)66−70 Only a subtle phase transition occurs in monoclinic L-cysteine.71 On increasing temperature up to 463− 468 K, the orthorhombic L-cysteine undergoes an irreversible phase transition into a less symmetric high-temperature phase.72 Boosting the capacity of −SH group to be a donor for S−H···O hydrogen bonding in oxalates and in N-acetyl-Lcysteine results in immobilizing the cysteine side chain and, as a consequence, in stabilizing the crystal structures with respect to phase transitions on cooling and on increasing hydrostatic pressure.73 The aim of the present study was to consider the dynamics of sulfhydryl groups and hydrogen bonds formed by them in the crystals of another small molecule, namely, homocysteine,

which differs from cysteine only by the presence of an extra −CH2− group in the side chain. The clinical significance of homocysteine has risen in the past few decades: elevated levels of homocysteine in the blood may be associated with atherosclerosis, an increased risk of cardiovascular diseases and even of Alzheimer’s disease and dementia74−77). Despite this obvious importance, in contrast with a large number of theoretical and experimental studies of cysteine, there was no information about molecular geometry or crystal packing of homocysteine published so far. Thus, in this work, the crystal structure and its dynamics were studied on cooling from ambient temperature down to 3 K by a combination of polarized Raman spectroscopy of oriented single-crystals and single-crystal X-ray diffraction. We were interested to know how the elongation of the side chain affects its lability and the capacity to form the S−H···X hydrogen bonds.

2. MATERIALS AND METHODS The sample of D,L-homocysteine was purchased from SigmaAldrich (CAS no. 454-29-5) as a fine powder. Most recrystallization experiments gave fine powder of the same phase. Several colorless plate-shaped crystals, suitable for singlecrystal X-ray diffraction, were selected from the polycrystalline sample obtained by slow (during a week) evaporation of saturated aqueous solution at 50 °C. The solution was slightly acidated by acetic acid to pH of ∼5.5 to minimize the oxidation of sulfhydryl group of homocysteine. To prevent the excessive ice growing at low temperatures, all mounted crystals for singlecrystal X-ray diffraction were covered with a thin layer of the low-viscosity CryoOil (Mitegen). X-ray Diffraction. Changes in the crystal structure of D,Lhomocysteine upon cooling were followed by single-crystal Xray diffraction using a Stoe IPDS-II diffractometer (Stoe & Cie, Darmstadt) equipped with a molybdenum X-ray tube (λKα = 0.71073 Å), a two-circle goniometer, an image plate detector, and an Oxford Cryostreams cooling device with temperature stability of ±0.1 K. Data sets were collected on cooling from 295 to 100 K with a temperature step of 20 K. Crystal structures at all temperatures were solved by direct methods using SHELXS78,79 and refined using SHELXL.80,81 All hydrogen atoms were found in difference Fourier maps. The isotropic displacement parameters of hydrogen atoms were set as 120% of Ueq (corresponding parent atom). The parameters characterizing data collection and refinement as well as crystal data are summarized in Table 1. Indexing of shapes of selected crystals for Raman spectroscopy experiments were done using procedure implemented in X-Shape software:82 the shortest crystal dimension (the height) coincided with the crystallographic axis c, whereas the width and the length of plate-shaped crystals corresponded to crystal axes a and b, respectively. The principal axes of the lattice strain ellipsoid were calculated using PASCal.83 Mercury84 and Platon85 were used for visualization, analysis, and inspection of the crystal structures at different temperatures. Structural data for D,L-homocysteine were deposited as CIFs at the Cambridge Crystallographic Database (CCDC no.: 993095-993105), and can be downloaded freely from the following site: http://www.ccdc.cam.ac.uk. These structures are also submitted as Supporting Information to the article. Raman Spectroscopy. Polarized Raman spectra of oriented single crystals of D,L-homocysteine were collected using a triple-grating Horiba Jobin Yvon Lab-Ram HP C



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torsion angles adopt gauche− conformation. In cysteinecontaining crystals, gauche conformation of the side chain is the most frequent one;56 gauche− conformation is inherent for crystals of D,L-cysteine under ambient conditions,52,63 D,Lcysteinium oxalate54 and L-cysteinium semioxalate,47 as well as for high-pressure phases of L-cysteine.57 At the same time, the conformation of the side chain of D,L-homocysteine differs from those in a hydrophobic structural analogue, norvaline, as well as in homoserine, where the sulfhydryl group is substituted for methyl and hydroxyl groups, respectively. In L-homoserine, χ1 and χ2 torsion angles are in trans and gauche+ conformations, although the conformation of the side chain in the crystals of both L- and D,L-serine is gauche+. Among the 12 conformers in nine crystal structures containing norvaline, the χ1 and χ2 torsion angles in each of the two conformers (Refcodes: “berner”,86 “zzzodu02”87) are characterized as trans and gauche, and those in the other two conformers are characterized as trans and trans (Refcodes: “zzzodu01” and “zzzodu02”87). In eight conformers (Refcodes: “berque”,86 “fitjex”,88 “golvim”,89 “povyij”,90 “uhepom”,91 “urodip”,92 “zzzodu01”, and “zzzodu02”87), the χ1 and χ2 torsion angles adopt gauche and trans conformations (based on the Cambridge Structural Database, version 5.34, May 201393). In Figure 2, it is clearly shown that

spectrometer equipped with a N2-cooled CCD-2048 × 512 detector Symphony from Jobin Yvon coupled to an Olympus BX41 microscope. Excitation was supplied by an Ar+ laser (35LAP431 from Melles Griot) with λ = 488 nm and spectral resolution of ∼2 cm−1. The low-temperature Raman spectra were recorded using a helium cryostat JANIS ST-500HT; oriented single-crystal samples of D,L-homocysteine were wrapped in a thin indium foil to provide a better thermal contact, so that only the upper crystal face was accessible for a laser beam. Raman spectra were measured on cooling from 295 to 5 K with a temperature step of 20 K. Temperature stability of gas flow during measurement better than 0.1 K was provided by a temperature controller, but the true temperature of the sample could be a little higher due to heating in a laser spot. (As estimated, in transparent crystals, this effect does not exceed 4 to 5 K.) The crystals were properly placed in the cryostat so that directions of the laser polarization vectors of an incident and scattered light coincided with each other and with the crystallographic axes of a crystal. The discrepancy between directions of laser polarization and the a and b crystallographic axes does not exceed 15°, although the crystal system is triclinic and two (α and γ) angles of the unit cell deviate significantly from the right angle. The polarized Raman spectra were measured and defined as c(aa)c, c(bb)c, and a(cc)a, according to the conventional notations of the polarized Raman spectra. Further in the text, the spectra are defined in a shortened way as just aa, bb, cc if the polarization was along a, b, and c crystallographic axes, respectively. (The directions of incident and scattered light are omitted for clarity.)

3. RESULTS AND DISCUSSION D,L-Homocysteine crystallizes in the centrosymmetric triclinic P-1 space group with two molecules per unit cell. Like other amino acids, D,L-homocysteine in the crystal exists as a zwitterion with positively charged amino group and negatively charged carboxylate group (Figure 1). The double bond in the

Figure 2. Conformations of side chains in D-enantiomers of norvaline (a−c) found in crystal structures deposited in CSD 93 and homocysteine (d): (a) Refcode “berner” with χ1 and χ2 torsion angles adopting trans and gauche;86 (b) Refcode “zzzodu02″ with χ1 and χ2 torsion angles adopting trans and trans;87 (c) Refcode “berque” with the most frequent combination of χ1 and χ2 torsion angles adopting gauche and trans;86 and (d) D,L-homocysteine with χ1 and χ2 torsion angles adopting gauche and gauche. All projections of zwitterions are chosen so that the αC−H bond is parallel to the viewing direction. Torsion angles χ1 and χ2 are schematically shown by green and red colors.

the χ2 torsion angle is more important for describing the linearity of the side chain. Thus, most zwitterions of norvaline (10 out of 12) have the “straight” conformation of the side chain, where the χ2 torsion angle corresponds to trans. The crystal structures of both norvaline and D,L-homocysteine are layered, and the “hooked” conformation of the side chain observed in homocysteine as well as in L-homoserine is caused most probably by “striving” sulfhydryl and hydroxyl groups to form hydrogen bonds with carboxylate groups. It is also interesting to notice that the previously suggested geometry of the homocysteine zwitterion, derived from the crystal structure of S-adenosyl-L-homocysteine,94 had a “straight” conformation of the side chain,95 which is not confirmed by the results obtained in the present work. Amino group of homocysteine is involved in three N−H···O hydrogen bonds. (The fourth hydrogen bond, N1−H3n···O1, is not taken into account because of the long H···O distance of 2.510(19) Å and a small N−H···O angle of 115.9(15)°, despite a proper N···O distance of 3.0053(17) Å.) The other two S− H···O hydrogen bonds are formed by sulfhydryl group.

Figure 1. Asymmetric unit of D,L-homocysteine showing the atom labeling scheme. Displacement ellipsoids are drawn at the 50% probability level; hydrogen atoms are present as fixed size spheres with radius of 0.3 Å.

carboxylate group is highly delocalized; C−O distances are practically the same (at ambient temperature the C1−O1 and C1−O2 are equal to 1.2567(18) and 1.2578(17) Å, respectively) and remain equal on cooling at least to 100 K. Conformation of the side chain can be characterized by two torsion angles N1−C2−C3−C4 (χ1) and C2−C3−C4−S1 (χ2): in L-enantiomer at ambient temperature their values are equal to −80.25(17) and −71.73(17)°, respectively; thus both D



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Table 2. Parameters of N−H···O and S−H···O Hydrogen Bonds in the Crystal Structure of D,L-Homocysteine at Ambient Temperature and at 100 Ka 295 K

a

100 K

hydrogen bond

D···A (Å)

D−H···A (deg)

D···A (Å)

D−H···A (deg)

N1−H1n···O2i N1−H2n···O1ii N1−H3n···O2iii S1−H1s···O1iv S1−H1s···O2ii

2.9511(18) 2.7689(16) 2.8740(18) 3.6480(14) 3.4635(13)

167.7(19) 170.3(18) 154.5(17) 143.8(16) 137.5(16)

2.9314(14) 2.7579(14) 2.8604(14) 3.5713(11) 3.4325(10)

166.8(16) 170.0(16) 154.9(16) 144.6(13) 136.8(13)

Symmetry codes: (i) −1 + x, y, z; (ii) x, 1 + y, z; (iii) 2 − x, 1 − y, 1 − z; and (iv) 1 + x, 1 + y, z.

Figure 3. Hydrogen bonding in the crystal structure of D,L-homocysteine: (a) a chiral part of a layer in (001) crystallographic plane formed by two straight infinite head to tail chains of the same chirality linked by N1−H1n···O2 and N1−H2n···O1 hydrogen bonds (colored by green and blue, respectively); (b) a projection of a layer at (010) crystallographic plane, N1−H3n···O2 hydrogen bond linking L- and D-zwitterions into finite R22(10) ring motif is colored by red. Other hydrogen bonds are shown as dotted blue lines. Hydrogen atoms of CH and CH2 groups are hidden for clarity. (Symmetry codes: (i): 1 + x, y, z; (ii), (iii), and (iv) correspond to that in Table 2).

O2, along the b crystallographic axis like infinite head-to-tail chains based on N1−H2n···O1 hydrogen bonds. The S···O distances in S1−H1s···O1 and S1−H1s···O2 hydrogen bonds are 3.6480(14) and 3.4635(13) Å, respectively. Both are significantly longer than those in orthorhombic and monoclinic polymorphs of L-cysteine, 3.3812(13)69 and 3.404(1) Å,51 respectively. A donor−acceptor distance of the shorter S1− H1s···O2 hydrogen bond in the structure is comparable to that in N-acetyl-L-cysteine (3.4699(7) Å73,97) and is much shorter than that in the low-temperature phase of D,L-cysteine (3.609(3) Å63) and D,L-cysteinium oxalate (3.6201(13) Å54). Thus, taking the structural data into account, one may conclude that in crystals of D,L-homocysteine at ambient temperature and pressure the hydrogen bonds formed by sulfhydryl groups are weaker than those in the two polymorphs of L-cysteine, comparable to those in N-acetyl-L-cysteine and stronger than those in the low-temperature/high-pressure phase of D,Lcysteine. Additional information about the crystal structure, especially about intermolecular hydrogen bonds, could be derived from Raman spectra. The study of oriented single crystals with polarized laser beam was of special interest because it greatly helped to assign Raman modes and to follow selected motions in the structure.63,69,98 Polarized Raman spectra of D,Lhomocysteine at ambient temperature and at 5 K are shown in Figure 4. It is clearly seen that most Raman bands are strongly polarized. Assignment in the low-wavenumber region is not so representative because the bands are not characteristic. However, taking into account previous spectroscopic studies of 59,63,69,99−102 L- and D,L-cysteine, one can distinguish the following spectral regions: 50−200 cm−1 is the range of lattice

Parameters of hydrogen bonds in the crystal structure of D,Lhomocysteine at ambient temperature are summarized in Table 2. The longest N1−H1n···O2 and the shortest N1−H2n···O1 hydrogen bonds form two straight infinite head to tail chains of C(5) type (common for amino acids) along crystallographic axes a and b, respectively (about graph-set notations; see ref 96). The links of these chains are related by the shortest translation and thus are of the same chirality. A fragment of the chiral part of a layer formed by N1−H1n···O2 and N1−H2n··· O1 hydrogen bonds is shown at Figure 3a. The middle N1− H3n···O2 hydrogen bond links L- and D-enantiomers of homocysteine into dimers of R22(10) type ring motif (Figure 3b). In this respect, the geometry of structural motifs formed by N−H···O hydrogen bonds in the crystals of D,L-homocysteine differs from that of D,L-cysteine because the latter has three infinite head to tail chains, two of which consist of L- and Denantiomers.63 The crystal structures of both D,L-homocysteine and D,Lcysteine are layered with strong N−H···O hydrogen bonds within layers and weak interactions between them. Similarity between the structures of D,L-homocysteine and the lowtemperature/high-pressure phase of D,L-cysteine is also in the formation of S−H···O hydrogen bonds in crystals (under ambient conditions, D,L-cysteine forms weaker S−H···S hydrogen bonds between layers),60 but in the case of D,Lhomocysteine, the sulfhydryl group participates in the formation of two S−H···O hydrogen bonds instead of one in D,L-cysteine and can be classified as three-centered or bifurcated hydrogen bond. S−H···O hydrogen bonds also form infinite chains of C(7) type in the structure: S1−H1s···O1 forms infinite chains along [110] crystallographic direction, S1−H1s··· E



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Figure 4. Polarized Raman spectra at ambient temperature (a) and at 5 K (b). The directions of polarization of incident and scattered laser beam coincide with each other, and with crystallographic axes a, b, and c, the corresponding Raman spectra are defined as aa, bb, and cc, respectively. The most intensive Raman bands are signed.

vibrations; 200−600 cm−1, skeletal vibrations of CCC, CCS, CCN as well as SHtors, NH3tors, COO−rock; 600−1000 cm−1, stretching vibrations of CS, CC, bending vibrations of COO−; 1000−1300 cm−1, SHbend, CH2twist, CH2wagg, CHbend; 1300− 1700 cm−1, CH2bend, COO−str, NH3bend. The band at 672 cm−1 could be assigned to CSstr because it has the highest intensity in aa polarization and the C−S bond is directed mainly along crystallographic axis a. Raman bands in the high-wavenumber region are more characteristic: the band at 2554 cm−1, which is most intensive in cc polarization corresponds to SHstr (S−H bond is along the c axis); several bands in the range of 2900− 3000 cm−1 are related to stretching vibrations of CH and CH2 groups. The band at 2912 cm−1 intensive in aa polarization could be assigned to C2−Hstr because this bond stretches mainly along axis a. Accordingly, the bands at 2934 and 2983 cm−1 could be assigned to C3−H2str.sym and C3−H2str.asym. Stretching vibrations of amino group are not pronounced in Raman spectra and overlap with CHstr bands, but the small and broadened band with the maxima at ∼3040 cm−1 in cc polarization corresponds to NHstr. The enlarged region of NHstr modes in the Raman spectrum shown in Figure 5 suggests that this broadened band can be fitted by at least two wide bands with maxima at 3018 and 3078 cm−1. On cooling down, the composite band becomes narrower and more intensive; in the Raman spectrum at 5 K, this band can be fitted by at least three components with maxima at 3019, 3037, and 3078 cm−1. For the shortest N1−H2n···O1 hydrogen

bond, one should expect lower values of the vibrational frequencies (∼2950 cm−1). The value falls in the range of C−H stretching vibrations, and this might explain why this mode is not observed in the spectra. The longest N1−H1n···O2 hydrogen bond should be related to a band at ∼3100 cm−1, but there is no evident band in this region in the spectra of aa polarization. Thus, the broadened band at ∼3040 cm−1 can be assigned to N−H3n stretching vibrations. At the same time, the component at 3037 cm−1 of this composite band should be assigned to N−H stretching vibrations in N1−H3n···O2 hydrogen bond, which is mostly directed along the c crystallographic axis; the presence of two other components may be caused by the effect of slow disordering of amino groups, particularly of the H3n protons, because of the influence of O1 acceptor to form N1−H3n···O1 hydrogen bond. Cooling leads to a decrease in the intensities of both components at 3019 and 3078 cm−1; the component at 3037 cm−1 dominates at 5 K. In contrast with D,L-cysteine, decreasing temperature does not result in a phase transition in D,L-homocysteine. The changes in the single-crystal X-ray diffraction data on cooling to 100 K as well as the changes in the Raman spectra on cooling down to 5 K are continuous. The reason for that lies in the presence of stronger S−H···O hydrogen bonds binding the side chain of homocysteine with a carboxylate group in the crystal structure already at ambient temperature, not allowing us to change the conformation of the side chain. The absence of a F



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phase transition in the crystals of D,L-homocysteine agrees with the previous work, showing that cysteine-containing crystal structures can be stabilized with respect to structural phase transitions by reducing the mobility of the side chain in the crystalline environment by different means, with the formation of S−H···O hydrogen bonds being one of them.73 The lowtemperature phase transition and the first phase transition induced by increasing pressure in the crystals of D,L-cysteine are related to the switching of hydrogen bonds formed by sulfhydryl groups from weak S−H···S to stronger S−H···O. This switching over is accompanied by a significant (∼5%) decrease in the distance between the layers in the structure during the phase transition, which is larger than could be expected based on the relative volume change (∼−2.7%).63 In D,L-homocysteine, the hypothetical switching of S−H···O hydrogen bonds to S−H···S ones (if it ever happened) would result in expanding the interlayer distance and changing the “hooked” conformation of the side chain into the “straight” one, which, in fact, does not take place on cooling. The changes in a, b, and c and the volume of the unit cell on cooling are plotted at Figure 6; the changes in the α, β, and γ triclinic angles do not exceed 0.5°. On cooling from ambient temperature to 100 K, the total volume decrease is 1.95(4)%. The largest linear strain (−1.58(4)%) is observed normal to the layers. The major contribution to this value comes from the decrease in the interlayer space between the side chains of the amino acid, that is, from the shortening of the distance between the two planes constituted from sulfur atoms (0.053(1) Å or 2.00(4)%), whereas the compression of the hydrophilic part of the layer (the distance between the two planes constituted by C1 atoms in the layer) is only 0.023(1) Å, or 0.79(4)%. The other two directions of the strain ellipsoid are practically in the (110) crystallographic plane. Their relative changes are, respectively, −0.47(4) and 0.08(4)% (a slight expansion).

Figure 5. Enlarged region of the Raman spectra measured at ambient and 5 K characterizing the stretching vibrations of amino group. Black line corresponds to the experimental Raman spectrum with cc polarization; red, blue, turquoise, and purple fitting lines correspond to different components of the broad band; dotted green line corresponds to the summarized fitting spectrum.

Figure 6. Changes of a, b, and c and the volume of the unit cell of the crystal structure of D,L-homocysteine on cooling. G



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Compression of the crystal structure of D,L-homocysteine on cooling does not lead to any changes in the conformation of zwitterions: the changes in the values of the NCCO, NCCC, and CCCS torsion angles do not exceed 0.6(1)°. The major contributions to structure compression come from the decrease in the volume of voids and the shortening of intermolecular hydrogen bonds. The shortening of different N−H···O hydrogen bonds on cooling is about the same, with the relative change ranging from −0.67(11)% (for the most compressible N1−H1n···O2 hydrogen bond) to −0.40(11)% (for the shortest and most rigid N1−H2n···O1 hydrogen bond). Unfortunately, because of the broadening of N−H stretching vibrations and their overlap with CHstr, it was hard to follow their shifts on cooling in the Raman spectra. However, the blue shift of NHbend (∼6 cm−1) on cooling to 5 K can serve as an indicator of the strengthening of the N−H···O hydrogen bonds. Hydrogen bonds formed by sulfhydryl groups are more compressible: S1−H1s···O2 shortens by 0.90(7)%, and the longer S1−H1s···O1 hydrogen bond shortens by 2.10(7)%, reaching the values of S···O distances, still larger than those in the monoclinic and the orthorhombic L-cysteine at ambient temperature. Thus, at 100 K, the S−H···O hydrogen bonds in the crystal structure of D,L-homocysteine continue being weaker than in L-cysteine polymorphs. The changes of the S···O distances in the S1−H1s···O2 and S1−H1s···O1 hydrogen bonds on cooling are shown in Figure 7. At the same time, the SHstr band shows a continuous blue shift of ∼6 cm−1, which is quite similar to the behavior of N-acetyl-L-cysteine on increasing hydrostatic pressure97 and can be explained in terms of strengthening of the bifurcated hydrogen bond. At ambient temperature, the values of the S−H···O angles in two hydrogen bonds are very close to each other (∼140°) and do not change significantly on cooling, but the longer S1···O1 distance is twice more compressible than the shorter one. Thus, one can see the symmetrization of the S···O distances, resulting in the increase in the role of the S1−H1s···O1 hydrogen bond in the competition between two O1 and O2 acceptors for the donor sulfhydryl group. Because the S1−H1s···O1 hydrogen bond itself is weaker than S1−H1···O2, the strengthening of S1−H1s···O1 hydrogen bond is not compensated by losing the priority of the S1−H1s···O2 hydrogen bond. The side chain participating in two hydrogen bonds at once is tightly bound within the hydrophilic part of the layers in the structure. Both the strengthening of the bifurcated S−H···O hydrogen bonds and the shortening of the interlayer distances on cooling decrease the free space needed for changing its conformation. One can compare this with the decrease in the interlayer distances because of changing the conformation of the side chain and switching of the S−H···S hydrogen bonds between layers to the S−H···O ones within the layer, which were observed during the phase transition on cooling in the crystals of D,L-cysteine.

Figure 7. Changes of the S···O distances in the S1−H1s···O1 (a) and S1−H1s···O2 (b) hydrogen bonds on cooling. A blue shift of stretching vibrations of S−H on cooling (c).

appearance of the bifurcated bond on increasing pressure to substitute a common two-centered S−H···O hydrogen bond present in the structure at ambient pressure.97 In the crystal of D,L-homocysteine, the bifurcated S−H···O hydrogen bond is present already at ambient temperature, and the blue shift on cooling results from its symmetrization (when the S···O distances become equal at the same S−H···O angles). There are several more examples, when the blue shift of SHstr band was measured in the Raman spectra (a high-pressure study of the orthorhombic L-cysteine58,59), or could be expected based on single-crystal structural data (high-pressure study of glutathione103). Strengthening of the bifurcated hydrogen bond in the structure can account for these observations, as has been supposed in ref 97. The phenomenon can be of interest also for biophysical research because the blue shift in the SHstr band of the sulfhydryl groups in cysteine-containing polymers can indicate the formation or strengthening of the bifurcated hydrogen bonds in the system.

4. CONCLUSIONS This study presents the second example (based on precise diffraction and spectroscopic data), which shows a blue shift of the stretching vibrations of the sulfhydryl group in cysteinecontaining crystals, accompanying a decrease in the S···O distances in the H bonds. The first reported example was provided by N-acetyl-L-cysteine.97 In both cases, the blue shift corresponds to the strengthening of the three-centered bifurcated S−H···O hydrogen bond in the structure. In the case of N-acetyl-L-cysteine, the blue shift is accompanied by the H



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ASSOCIATED CONTENT

S Supporting Information *

Structural data for D,L-homocysteine. This material is available free of charge via the Internet at http://pubs.acs.org. These structures are also deposited as CIFs at the Cambridge Crystallographic Database (CCDC no.: 993095-993105) and can be downloaded freely from the following site http://www. ccdc.cam.ac.uk.

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AUTHOR INFORMATION

Corresponding Authors

*V.S.M.: E-mail: [email protected]. *E.V.B.: E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support from the Russian Academy of Sciences and from the Novosibirsk State University.

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REFERENCES

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