The Chirality Chain in Valine: How the Configuration at the C_α Position through the O_cisC′C_αN Torsional System Leads to Distortion of the Planar Group C_αC′(O_cis)O_trans to a Flat Tetrahedron

Abstract

Solid‐state structures, based on a Cambridge Structural Database (CSD) search, show that there is a C_αN/C′O_cis attraction in the torsional system O_cisC′C_αN of valine, causing a chirality chain. The C_α configuration controls the chirality of the rotation around the C′−C_α bond, which in turn induces a distortion of the planar unit C_αC′(O)O to a flat asymmetric tetrahedron. Conformational “reactions” take place in an energy profile with respect to clockwise and counterclockwise rotation around the C′−C_α bond as well as stretching and flattening of the tetrahedron. The molecular property C_αN/C′O_cis attraction of valine is maintained in its di‐ and tripeptides.

Natural amino acids with their inherent molecular properties are the building blocks of proteins. Herein, we show that for valine, the chirality chain from the configuration at the C_α position through the torsional system O_cis−C′−C_α−N, leads to the distortion of the planar group C_αC′(O_cis)O_trans to a flat tetrahedron.

A search in the Cambridge Structural Database for H₃N−CH(iPr)−C′(O)O gave 68 hits, with 28 structures containing independent molecules. Thus, 105 cases are available for analysis (these are collected in Tables S1 and S2 in the Supporting Information). As these tables comprise up to 65 entries, truncated Table 1 and Table 2 are used in this Communication.

Table 1.

Zwitterionic valine structures.

Entry	CSD symbol[a]	Chirality chain			Distances [Å]		Attraction CαN/C′O angles [°]		Comments
		Config. Cα	Ocis‐C′‐Cα‐N rotation angle ψ [°]	Otrans‐C′‐Cα‐Ocis pyramidal angle θ [°]	Ocis−N	Ocis−C(iPr)	N‐Cα‐C′(O)	(iPr)C‐Cα‐C′(O)
1	LVALIN01(1)	L	−17.48	−177.78	2.66	3.39	109.26	112.72	enantiomer(1)
4	VALIDL03	L	−23.31	−179.09	2.67	3.33	110.02	112.47	racemate[b]
8	LVALIN01(2)	L	−42.81	−177.66	2.76	3.10	109.33	110.48	enantiomer(2)
12	AHEJEC(1)[c]	D	17.95	177.75	2.66	3.38	109.31	112.98	enantiomer(1)
18	AHEJEC03(2)[c]	D	43.99	177.82	2.75	3.09	109.23	110.74	enantiomer(2)
20	OPEFUL[1]	L	−5.53	−181.00	2.60	3.51	107.19	116.10	+l‐valine⋅HCl adduct
25	GUQJUZ[1](2)	L	−20.39	−177.28	2.64	3.30	107.90	112.64	+valine⋅naphthalene‐ 1,5‐(SO3H)2 adduct
30	GOLVUY	L	−35.59	−177.34	2.69	3.17	108.04	110.44	+d‐n‐BuAA[d]
40	SONCED[c]	D	25.84	179.48	2.68	3.31	109.52	112.63	+l‐phenylalanine
	average		−27.74	−178.32	2.69	3.28	108.86	111.95

[a] Parenthesis () indicate independent molecules in the unit cell, whereas brackets [] differentiate between ⁺NH₃CH(ⁱPr)COO⁻ and ⁺NH₃CH(ⁱPr)COOH. [b] Racemates given as l‐compounds. [c] For average calculation rotation angle and distortion angle are inverted. [d] AA=amino acid.

Table 2.

Valine zwitterions protonated at the carboxylic group by strong acids.

Entry	CSD symbol[a]	Chirality chain			Distances [Å]		Attraction CαN/C′O angles [°]		Comments
		Config. Cα	Ocis‐C′‐Cα‐N rotation angle ψ [°]	Otrans‐C′‐Cα‐Ocis pyramidal angle θ [°]	Ocis−N	Ocis−C(iPr)	N‐Cα‐C′(O)	(iPr)C‐Cα‐C′(O)
1	WIHQUA(1)	L	1.77	−182.10	2.66	2.66	107.24	111.77	H2NbOF5
8	VALHCL10	L	−3.72	−182.11	2.68	2.68	108.41	109.80	HCl, H2O
16	TUZJIJ	L	−11.44	−177.98	2.65	2.65	107.86	110.89	TsOH, H2O
24	WIHQUA(2)[b]	L	−15.68	−178.90	2.68	2.68	107.69	113.46	H2NbOF5
32	BANPOW(4)	L	−20.98	−177.94	2.69	2.69	107.69	110.13	HClO4
40	DUMZOB	L	−25.00	−179.10	2.71	2.71	107.07	113.47	HCl, Bn ester
48	ROKBOI(2)	L	−32.49	−179.22	2.76	2.76	108.63	109.72	HNO3
56	ESAPET01(1)	L	−14.91	−179.54	2.65	2.65	110.26	112.59	H2PbO3, 2HNO3, H2O
65	VALCAC	L	−35.46	−179.94	2.67	2.67	105.99	110.48	CaCl2(H2O)
	average		−18.69	−179.06	2.67	3.36	107.69	112.38

[a] Parenthesis () indicate independent molecules in the unit cell. [b] Racemates given as l‐compounds.

There are 40 structure determinations of valine in its zwitterionic form (see Table S1). Three representative examples of pure valine racemate and enantiomers are given at the beginning of Table 1. The valine enantiomers have two independent molecules in the unit cell, differentiated by parentheses. The second part of Table 1 contains zwitterionic valine structures in different environments, selected such that Table 1 does not exceed ten entries.

We determined the torsion angles ψ=O_cis−C′−C_α−N of the valine racemate (Table 1, entry 4) and enantiomers (entries 1 and 8). We differentiate the oxygen atoms of the carboxylic group as O_cis and O_trans according to their orientation with respect to the amino nitrogen atom (Figure 1 A). As the torsion angles ψ measure the rotation around the C_α−C′(O)O bond, we call them rotation angles. For l‐valine in enantiomers and racemates the rotation angles ψ are negative (Figure 1 A), for d‐valine they are positive. A four‐atom system such as O_cis−C′−C_α−N is chiral, unless the torsion angle ψ is 0 or 180°. According to the helicity rule of the CIP system,1 positive rotation angles result in (P)‐conformation and negative angles in (M)‐conformation.

Figure 1.

A) Rotation angles ψ=O_cis−C′−C_α−N in the zwitterionic racemate and enantiomers (dashed) of l‐valine (Table 1, entries 1, 4, 8), looking down the C′−C_α bond (symbol C′_α). B) Distortion of the planar system C_αC′(O)O to a chiral flat tetrahedron (exaggerated). C) Attraction C_αN/C′O: bending of C′−O_cis towards C_α−NH₃. D) Conformation of valine in di‐ and tripeptides.

The central carbon atom of the carboxylic group of valine is sp²‐hybridized. Thus, the unit C_αC′(O)O should be planar and achiral. However, a deviation from planarity results in a flat tetrahedron, which is chiral, due to its four different corners C′, C_α, O_cis, and O_trans (Figure 1 B). A measure of its chirality is the torsion angle θ=O_trans−C′−C_α−O_cis. The torsion angles θ will be called pyramidalization angles. They determine the deviation of O_cis from the plane O_trans−C′−C_α (Figure 1 B and 1C) due to the attraction C_αN/C′O (see below). The configuration of the flat tetrahedron will be specified by (R)/(S) according to the priority sequence O_cis>O_trans>C′>C_α of the CIP system.1 For valine in peptides the priority sequence is O>N>C′>C_α. The flat tetrahedron in Figure 1 B and 1C has (S)‐configuration. Thus, the complete stereochemistry of l‐valine in enantiomers and racemates is L(M)(S) and that of d‐valine is D(P)(R).

In the tables, all the hits of the CSD search are included irrespective of old/new, low/high quality, because each hit is an individual structure determination. Multiple analyses help to evaluate small effects such as tetrahedral distortions. For the relatively large pyramidalization angle θ=177.10° of AHEJEC03(2) (Table S1, entry 18), the deviation of O_cis from the plane O_trans−C′−C_α amounts to 0.021 Å. However, the following analysis will show that both the induction from the given chirality at C_α to the torsional system O_cisC′C_αN and from the torsional system to the pyramidalization of the planar group C_αC′(O)O occurs with high diastereoselectivity.

The second part of Table 1 shows structures in which the valine zwitterion crystallizes together with l‐valine molecules protonated by strong acids or co‐crystallizes with natural and unnatural amino acids. In all cases the induction chain L→(−)→(−) is perfect. In the 40 cases of Table S1, there is one example in which the rotation angle ψ adopts a small positive value, inducing (P)‐configuration in the flat tetrahedron. Concerning the induction from the torsional system to the flat tetrahedron there are four exceptions (θ>−180°).

In entries 1–40 of Tables 1 and S1 the valine zwitterion is in completely different environments. Irrespective of the changing packing and hydrogen‐bond networks, a unique structural motif is common to all structures, the chiral induction chain. The given l/d‐chirality at the C_α position controls the arrangement of the torsional system O_cisC′C_αN in the narrow range from 3.49° to −53.26° of rotation angles ψ. The other 303° of the full circle are not occupied by sample points. The torsional system O_cisC′C_αN in turn induces the preferred (S)‐configuration in the flat tetrahedron with high selectivity.

Strong acids protonate valine at the carboxylic group to give salt‐like structures with the cation H₃N‐CH(iPr)‐C′(O)OH⁺. In all the structures of Tables 2 and S2 (54 cases), protonation occurs on the O_trans atom except for HOSMEA (entry 54). In three cases, the O_trans centre is alkylated to give the methyl and benzyl esters (entries 39, 40, and 46). Protonation and alkylation differentiate O_cis and O_trans with respect to the lengths of the C′−O bonds. The C′−O bonds are much longer in the COH/R system compared to the C=O group.

The range of rotation angles ψ in Tables 2 and S2 from 1.77° to −43.91° is even a little narrower than in Tables 1 and S1. According to the chirality chain, the two slightly positive rotation angles in entries 1 and 2 induce positive pyramidal angles. The 49 negative rotation angles from entry 3 to entry 52 in the l‐valine series result in negative pyramidal angles (9 exceptions; θ>−180°). Thus, the results in Tables 2 and S2 corroborate the high selectivities in protonation as well as rotation and pyramidalization angles.

At the end of Table S2 (see the Supporting Information) eleven structures are listed in which valine zwitterions coordinate as ligands in metal complexes. The induction from the C_α position to the torsional system O_cisC′C_αN is perfect; from the torsional system to the flat tetrahedron there are two exception (θ>−180°).

In Table S1 (see the Supporting Information) there is one l‐Val with a positive rotation angle and Table S2 contains two l‐Val entries with slightly positive rotation angles. They are the positive parts of the range from −53.26° to 3.49°, which is well in agreement with the fact that the C_α configuration confers induction onto the torsional system O_cisC′C_αN. However, the chirality of the torsional system O_cisC′C_αN changes from (M) for −53.26–0° to (P) for 0–3.49°.

In the torsional system O_cisC′C_αN of the valine zwitterions, the C_α−NH₃ bond is close to eclipsing the C′−O_cis bond, indicating an attraction C_α−NH₃/C′−O_cis. This is evident in the small negative rotation angles ψ (average ψ=−27.74° in Table S1, ψ=−18.69° in Table S2, and average ψ=−22.13° in Tables S1 and S2, see the Supporting Information). We think the attraction is due to NH…O_cis hydrogen bonding.

The attraction C_α−NH₃/C′−O_cis should manifest itself also in structural parameters like distances and bond angles. In the torsional system O_cisC′C_αN, proof for an attraction comes from the distances O_cis−N and O_cis−C(iPr) in Tables 1 and S1 and Tables 2 and S2 (columns 6 and 7; see the Supporting Information). Increasing the rotation angle ψ from 0 to −53° should increase the distances O_cis−N and decrease the distances O_cis−C(iPr) in the same way. However, excluding the outlier 2.48 Å (see Table S2, entry 13 in the Supporting Information), the interval of the distances O_cis−N spans only 0.2 Å from 2.60–2.82 Å, whereas the interval of the distances O_cis−C(iPr) overstretches 0.6 Å from 3.00–3.60 Å. This shows that the torsional system O_cisC′C_αN resists elongation of the distance O_cis−N by adjusting bond lengths and angles such as to keep the distance O_cis−N as constant as possible. As the van der Waals radii of O and N are 1.55 and 1.60 Å,2 the O_cis−N distances are far below the sum of the van der Waals radii, indicating an attractive interaction in the torsional system O_cisC′C_αN.

In columns 8 and 9 of Tables 1 and S1, the bond angles N‐C_α‐C′(O) and (iPr)C‐C_α‐C′(O) are compared. The N‐C_α‐C′(O) angles are generally below the tetrahedral angle (average 108.86°; see Table S1) and smaller than the (iPr)C‐C_α‐C′(O) angles, which are above the tetrahedral angle (average 111.95°). Tables 2, 2 and Tables S2 and S3 show the same trends. As the size of the isopropyl substituent could be a reason for the large angles (iPr)C‐C_α‐C′(O), we checked the 78 zwitterionic structures of alanine in the CSD. In alanine, C_α−NH₃ and C_α−CH₃ have similar sizes. The averages of the angles H₃N‐C_α‐C′(O) and H₃C‐C_α‐C′(O) in alanine are 109.70° and 111.44°,3 confirming the attraction C_α−NH₃/C′−O_cis, which in turn is the reason for the chirality transfer from the C_α configuration to the torsional system O_cisC′C_αN.

Thus, distances and torsion as well as bond angles prove the attraction C_α−NH₃/C′−O_cis, in which C′−O_cis and C_α−NH₃ bend towards each other (Figure 1 C) in valine and also in alanine.

The 105 sample points of Tables S1 and S2 are shown in the histogram of Figure 2. l‐compounds crowd in the lower right quadrant. In Figure 2 the d‐compounds are inverted to l‐compounds. Exceptions appear in the lower left quadrant. The best‐fit line of the 102 compounds with negative rotation angles indicates a good correlation of rotation and pyramidalization angles (step 2 of the chirality chain). The best‐fit line is additional proof for the attraction C_α−NH₃/C′−O_cis. It shows that the more the O_cis centre is removed from the perpendicular plane O_transC′C_α in Figure 1 C, the larger the torsion angle ψ.

Figure 2.

Histogram of the correlation of rotation angles (ordinate) and pyramidalization angles (abscissa) of the 105 sample points of Tables S1 and S2. d‐compounds inverted to l‐compounds (R ²=0.2944, ρ<3.85×10⁻⁹;102 compounds with negative rotation angles).

Movement along the best‐fit line in Figure 2 describes readily occurring conformational changes as exemplified for the “reaction” HURXEX(1) → ROKBOI02(4). The descent from HURXEX(1) to ROKBOI02(4) along the best‐fit line implies a rotation around the C′−C_α axis in a specific direction and an increasing distortion of the flat tetrahedron. Rotation around the C′−C_α axis of HURXEX(1) from −11.68° to −43.91° of ROKBOI02(4) is a counter‐clockwise (c‐clw) movement of 32.23°. It is associated with a stretching of the flat tetrahedron, indicated by an increase of the pyramidalization angle from 179.51° to 176.71° (Figure 3). The other way round, the ascent from HURXEX(1) to ROKBOI02(4) is a clockwise rotation around C′−C_α combined with a compression of the flat tetrahedron.

Figure 3.

Conformational “reactions” HURXEX(1)→ROKBOI02(4) and ROKBOI02(4)→HURXEX(1).

In Figure 3 the reaction HURXEX(1) → ROKBOI02(4) is embedded in an energy profile with respect to rotation around the C′−C_α bond in valine. The accumulation of sample points is interpreted as the energy minimum.4, 5 Following the arrows towards the energy minimum, conformations of type HURXEX(1) rotate preferentially counter‐clockwise stretching the flat tetrahedron, whereas those of type ROKBOI02(4) rotate clockwise flattening the tetrahedron.

Table 3 summarizes rotation and pyramidalization angles as well as distances and bond angles of valine‐containing tripeptides (Figure 1 D). There is not much difference between valine at the amino end, in the middle or at the carboxy end and the results are well in line with the valine structures in Tables S1 and S2.

Table 3.

Valine in tripeptides.

Entry	CSD symbol[a]	Tripeptide	Chirality chain			Distances [Å]		Attraction CαN/C′O angles [°]		Comments
			Config. Cα	Ocis‐C′‐Cα‐N ψ [°]	Otrans(Namide)‐C′α‐Ocis θ [°]	Ocis−N	Ocis−C(iPr)	N‐Cα‐C′(O)	(iPr)C‐Cα‐C′(O)
1	DVLTLV10[b]	Val‐Trp‐Val	DLL	15.58	177.88	2.87	3.07	107.25	110.44	amino end (D)
2	AQOWAE	Val‐Gly‐Gly	L	−0.79	−179.35	2.70	3.52	109.44	111.35	carboxy end, HCl
3	BEVYIL	Val‐Val‐Val	LLL	−31.74	−176.74	2.75	3.26	109.74	109.47	carboxy end, CF3COOH
4	XEPZAU(1)	Val‐Ile‐Ala	LLL	−42.92	−177.06	2.74	3.15	107.71	112.67
5	BEVYIL	Val‐Val‐Val	LLL	−43.80	−176.67	2.76	3.06	107.23	108.82	amino end, CF3COOH
6	XEPZAU(2)	Val‐Ile‐Ala	LLL	−44.68	−174.99	2.74	3.08	107.34	110.63
7	XEPZAU(3)	Val‐Ile‐Ala	LLL	−46.51	−178.50	2.74	3.05	105.97	110.19
8	XEPZAU(4)	Val‐Ile‐Ala	LLL	−47.69	−177.44	2.76	3.05	106.91	110.16
9	BEVYIL	Val‐Val‐Val	LLL	−50.01	−177.49	2.81	3.06	108.95	110.31	carboxy end
10	CUWRUH	Gly‐Gly‐Val	L	−50.71	−180.21	2.86	3.11	110.28	111.96
11	DVLTLV10	Val‐Trp‐Val	DLL	−52.20	−178.29	2.62	3.35	110.03	111.68	carboxy end (L)
12	BEVYIL	Val‐Val‐Val	LLL	−54.03	−178.68	2.82	3.03	106.78	109.25	middle CF3COOH
13	BEVYIL	Val‐Val‐Val	LLL	−54.47	−176.94	2.89	2.96	106.41	108.78	amino end
14	COPBIS10	Val‐Gly‐Gly	L	−58.32	−178.58	2.86	3.00	107.05	110.78	amino end
15	BEVYIL	Val‐Val‐Val	LLL	−58.51	−179.75	2.84	3.01	106.02	110.55	middle
	Average			−43.46	−177.91	2.78	3.12	107.81	110.47

[a] Parenthesis ( ) indicate independent molecules in the unit cell. [b] For average calculation rotation angle and pyramidalization angle inverted.

All the rotation angles of valine in the tripeptides are negative except for entry 1 (Table 3), which contains d‐valine at the amino end. They span the typical range from −0.79° to −58.51°. The (M)‐torsional system induces (S)‐chirality in the flat tetrahedron with one exception, the value −179.8° of which is close to −180°. The distances O_cis−N are short and the bond angles N‐C′‐C_α are far below the tetrahedral angle due to the attraction C_αN/C′O_cis.

As the analysis of valine‐containing dipeptides comprises 78 examples, Table S3 is given in the Supporting Information. The results correspond to those obtained up to now. The range of rotation angles is from 6.45° to −71.60° except for MOBYEH, which contains 8 independent molecules, four of which have the expected small negative rotation angles. However, four MOBYEH molecules have the unfavorable syn‐conformation with respect to the C′−C_α bond, which entails large rotation angles. The selectivity of distortion of the flat tetrahedron is better than 80 %. The distances O_cis−N and O_cis−C(iPr) as well as the angles N−C′−C_α and (iPr)C−C_α−C′(O), confirming the attraction C_αN/C′O_cis, are comparable to Tables S1 and S2.

Pyramidalization of the unit C_αC′(O)O in Val is caused by the C_α−N/C′−O_near attraction. There are other weak interactions, resulting in pyramidalizations, for example, n→π* interactions. In proteins, the approach of an adjacent C=O group to the C′ position of a carboxamide below 3.22 Å is considered a weak non‐covalent n→π* attraction.6 In the dipeptides of Table S3, three such pyramidalizations by n→π* interactions are present (entries 5, 10, 28).

The small negative ψ angle and the induced (S)‐pyramidalization, controlled by the configuration at the C_α position and the attraction C_α−N/C′−O_cis, are inherent properties of the l‐Val molecule, which may be overruled in proteins by other effects. Thus, valine enters into α‐helix domains with small negative ψ angles and (S)‐pyramidalization. However, when valine is used as a building block in β‐sheet domains, dramatic changes in the ψ angles and a chirality change of the pyramidalization takes place.7, 8

As other amino acids show similar effects as valine, further studies are in progress.

Experimental Section

The Cambridge Structural Database ver. 5.399 (update May 2018) was used for a search of the compounds in Tables 1–3 and Tables S1–S3. The programs OLEX ²,10 Mercury CSD ver. 3.10.2,11 and ConQuest ver. 1.2212 were used for the structure analyses.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supplementary

H. Brunner, T. Tsuno, ChemistryOpen 2018, 7, 696.