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Proc Natl Acad Sci U S A. Jul 31, 2001; 98(16): 9056–9061.
PMCID: PMC55372
Biophysics

The Cα—H[center dot][center dot][center dot]O hydrogen bond: A determinant of stability and specificity in transmembrane helix interactions

Abstract

The Cα—H[center dot][center dot][center dot]O hydrogen bond has been given little attention as a determinant of transmembrane helix association. Stimulated by recent calculations suggesting that such bonds can be much stronger than has been supposed, we have analyzed 11 known membrane protein structures and found that apparent carbon α hydrogen bonds cluster frequently at glycine-, serine-, and threonine-rich packing interfaces between transmembrane helices. Parallel right-handed helix–helix interactions appear to favor Cα—H[center dot][center dot][center dot]O bond formation. In particular, Cα—H[center dot][center dot][center dot]O interactions are frequent between helices having the structural motif of the glycophorin A dimer and the GxxxG pair. We suggest that Cα—H[center dot][center dot][center dot]O hydrogen bonds are important determinants of stability and, depending on packing, specificity in membrane protein folding.

The hydrogen bond is a key element in the interplay between stability and specificity in protein folding. The desolvation penalty associated with burial of polar side chains in an aqueous environment is not always fully recovered by hydrogen bond formation, so hydrogen bonds provide a small or even unfavorable net energy contribution to folding. However, the strength and directionality of hydrogen bonds make them an important factor in discriminating between correctly folded and misfolded states. Hence, polar interactions tend to contribute more to specificity than to stability in soluble proteins (13). Conversely, in the apolar environment of biological membranes donor and acceptor groups cannot be satisfied by the solvent, and hydrogen bonds strongly stabilize the helical conformation of membrane spanning domains (4) and can stabilize tertiary interactions as well (59). We are interested in the role of hydrogen bonds in the association of transmembrane helices, a stage that is pivotal in the folding of membrane proteins (4). Recently, the DeGrado group and our laboratory showed that the substitution of a single polar amino acid residue into model transmembrane helices induces homo-oligomerization (1013); the association driven by hydrogen bonding can be strong and independent of packing details. Thus, in the apolar environment, the strength of hydrogen bonds can stabilize the association of transmembrane helices, although a lack of a need for sequence specificity could create a danger of inducing promiscuous association (10, 13).

Weaker hydrogen bonds, such as those between carbon and oxygen atoms (C—H[center dot][center dot][center dot]O), have received little attention in the membrane protein field, and their occurrence in membrane proteins has never been surveyed. The Cα is an activated carbon donor because it is bound to the electron-withdrawing amide N—H and C==O groups, and, in soluble proteins, hydrogen bonds between main-chain Cα—H groups and backbone or side-chain oxygen atoms are often observed (1417). Despite its abundance, the structural contribution of the Cα—H[center dot][center dot][center dot]O hydrogen bond has been unclear and its interaction energy has been believed to be small. Recently, by using ab initio calculations, Vargas et al. (18) and Scheiner et al. (19) estimated the energy of the Cα—H[center dot][center dot][center dot]O hydrogen bond to be as much as 2.5–3.0 kcal/mol in vacuo, placing the strength of the Cα—H[center dot][center dot][center dot]O hydrogen bond at approximately one-half the energy of a “conventional” N—H[center dot][center dot][center dot]O hydrogen bond. Given the importance of electrostatic interactions in the apolar interior of a membrane lipid bilayer, this energy may be significant for providing stability in transmembrane helix–helix association, especially when several Cα—H[center dot][center dot][center dot]O interactions are coordinated at a single interface. To examine this hypothesis, we have analyzed 125 helix–helix interfaces in a database of 11 nonhomologous membrane protein structures (Table (Table1)1) in search of Cα—H[center dot][center dot][center dot]O contacts that display the geometric hallmarks of hydrogen bonds. The analysis is limited by the uncertainty in the positioning of atoms in crystal structures solved at 2- to 3-Å resolution, although even at these resolutions the position of backbone atoms and helix axes should be quite accurate. We find recurring patterns when Cα—H[center dot][center dot][center dot]O contacts cluster at interfaces between helices that display a short interaxial distance, have a preference for parallel right-handed packing, and are rich in glycine, serine, and threonine residues. Our results suggest that Cα—H[center dot][center dot][center dot]O hydrogen bonds are overlooked factors that can determine stability and, given their dependence on the packing details, also specificity in the interaction of transmembrane helices.

Table 1
Structural database of nonhomologous helical membrane proteins

Methods

Our database of 11 nonhomologous helical membrane proteins is listed in Table Table1.1. Hydrogen atoms were added to the crystallographic protein database coordinate files with the program REDUCE (20). Identification of the helical segments was performed with the program DSSP (21). For homo-oligomers, only a single representative of the duplicated helix–helix interaction was considered. The structural analysis of Cα—H[center dot][center dot][center dot]O contacts (distances dH and d and angles ζ, ξ, and θ, nomenclature according to Derewenda et al. (14), defined in Fig. Fig.11A) and the calculations of interhelical distances and angles were performed with a custom-made PERL program (available from the authors on request). Interhelical angles and axial distances were calculated at the point of minimal axial distance by using the local helical axis. The local helical axes were calculated by using the coordinates of four contiguous Cα atoms according to Sugeta and Miyazawa (22) with a PERL subroutine adapted from the FORTRAN program HELANAL (23).

Figure 1
(A) Definition of the geometrical parameters of the Cα—H[center dot][center dot][center dot]O hydrogen bond. Nomenclature according to Derewenda et al. (14). The ideal values (14, 18) are as follows: H—O distance, dH ≤ 2.7 Å; ...

Results and Discussion

Distribution of Interhelical Cα—H[center dot][center dot][center dot]O Hydrogen Bonds in Transmembrane Helices.

The optimal geometry for a strong Cα—H[center dot][center dot][center dot]O hydrogen bond is described in Fig. Fig.11A. The H[center dot][center dot][center dot]O distance (dH) should be smaller than 2.7 Å (the sum of the van der Waals radii), and all three atoms should be aligned (C—H—O angle ζ = 180°) (14, 17, 18). We calculated the dH distribution of all Cα hydrogen donors to backbone and side chain acceptors in our database of membrane proteins and compared it to that obtained with a similarly sized set of aliphatic Cβ and Cγ hydrogen atoms (Fig. (Fig.11B). The ratio of the two distributions shows that Cα hydrogen atoms form contacts below van der Waals separation more frequently (overall, 3 times more frequently below 2.7 Å). This is consistent with the fact that the Cα is an activated carbon donor with a higher tendency to form C—H[center dot][center dot][center dot]O hydrogen bonds. Despite the lower sample size, a similar trend is observed when the analogous distribution is calculated limited to the subset of donors and acceptor groups of transmembrane helical segments (Fig. (Fig.11C).

We studied the geometry of interaction of all potential Cα—H[center dot][center dot][center dot]O hydrogen bonds between transmembrane helical segments. Hydrogen bond interactions persist at a longer range than van der Waals separation and tolerate significant angular distortion (17). Operatively, we selected dH < 3.5 Å and ζ > 120° (or ζ > 90° when dH < 3.0 Å) as a comprehensive limit for recording Cα—H[center dot][center dot][center dot]O contacts as potential hydrogen bonds. We found 145 interhelical Cα—H[center dot][center dot][center dot]O contacts, 51 of which have dH < 2.7 Å in 125 helix–helix interactions between 103 helices (Table (Table1).1). About one-fourth of all helix–helix interactions contain at least two instances of interhelical Cα—H[center dot][center dot][center dot]O contacts to either backbone or side-chain oxygen acceptors. One-tenth contain at least two backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C contacts. The distribution of these subsets of helix–helix interactions as a function of packing angle (Ω) is displayed in Fig. Fig.22A. In the total set of interactions (blue) we found a strong bias for left-handed packing, as in an earlier analysis by Bowie (24). The bias is mainly because of the antiparallel component (57 left- vs. 25 right-handed). When one considers only those helix–helix interactions with a minimum of two Cα—H[center dot][center dot][center dot]O contacts to backbone or side-chain acceptors (red), some preference for right-handed parallel and left-handed antiparallel interactions appears. When a further requirement of at least two backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C contacts is introduced (yellow), a dramatic selection for right-handed parallel interactions is seen (χ2 test, P < 0.005). Notably, in the −50° to −20° range of packing angles, ≈50% of all helix–helix interactions persist after the selection. Thus, parallel right-handed packing favors interhelical backbone-to-backbone contacts and Cα—H[center dot][center dot][center dot]O formation.

Figure 2
(A) Distribution of interhelical packing angles (Ω). Interhelical packing angles were calculated as the angle between the local helical axes at the point of minimal axial distance. L-H, left-handed; R-H, right-handed; blue, all helix–helix ...

The analysis of the occurrence of Cα—H[center dot][center dot][center dot]O contacts as a function of the interhelical axial distance is shown in Fig. Fig.22B. All interhelical distances in the database are between 6 and 12 Å with an average of 8.9 Å. The average drops to 7.8 Å when at least two Cα—H[center dot][center dot][center dot]O contacts are present and it is further reduced to 7.0 Å when at least two backbone-to-backbone contacts are present (with no instance above 7.6 Å). Notably, below 7.0 Å all helix–helix interactions contain potential Cα—H[center dot][center dot][center dot]O==C backbone-to-backbone bonds.

Parallel Right-Handed Helix–Helix Interactions: Occurrence of Glycophorin A (GpA)-Like Motifs with Multiple Cα—H[center dot][center dot][center dot]O Bonds.

Four cases of parallel right-handed helix–helix interactions with extended Cα—H[center dot][center dot][center dot]O contacts are present in the database (Fig. (Fig.3).3). Two cases are found in the glycerol facilitator (GlpF) (25); a third example is observed in the calcium ATPase (26); and the fourth is found in the GpA dimer (27). The geometries of the Cα—H[center dot][center dot][center dot]O contacts are shown in Table Table22 together with the ideal distance and angle values. Cα—H[center dot][center dot][center dot]O hydrogen bonds can tolerate some divergence from ideality (18), and steric factors imposed by helical packing may prevent ideal geometry. The four helix–helix interactions display very similar packing angles (−29° to −40°). The interactions also have similar interfacial residues: pairs of small residues spaced at i, i + 4 are present on all helices and, in particular, GxxxG motifs (2830) are observed in all but one interface (a SxxxG motif is found in helix 4 of GlpF). As discussed later, the GxxxG motif is known to drive transmembrane helix association.

Figure 3
Parallel right-handed helix–helix interactions with extended networks of Cα—H[center dot][center dot][center dot]O contacts (GpA-like motifs). (A) Schematic representation of the structure of the glycerol facilitator (GlpF, Protein Database ...
Table 2
Geometry* of Cα—H[center dot][center dot][center dot]O contacts in GpA-like motifs

Although the four right-handed structures have similar packing angles and interfacial residues, they, most strikingly, also share a pattern of Cα—H[center dot][center dot][center dot]O connectivity. In Fig. Fig.44A, the backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C contacts are represented by black arrows, and the backbone-to-side chain Cα—H[center dot][center dot][center dot]O contacts by gray arrows. All backbone-to-backbone contacts occur with the same periodicity, between one residue and two residues spaced at i, i + 4 on the opposite helix. The i, i + 4 connectivity extends up to three helical turns. The GxxxG interaction motifs are central to this connectivity, as highlighted in the backbone superimposition of the four structures in Fig. Fig.44B. The four connecting atoms used to align the structures are displayed in ball representation. On the right are shown the helices containing the GxxxG (SxxxG) motifs with the carbonyl oxygen of the Gly at i (4) and the Cα of the Gly at i + 4 (1); on the left, the Cα (3) and the oxygen (2) of the residue that interacts with the two Gly residues. The interhelical packing angles of −29° to −40° appear to favor the i, i + 4 connectivity. The relative rotation that has to be applied to two opposing helices to align the vector joining the Cα and the carbonyl oxygen of a residue on one helix (vector 2-3), with the vector joining a carbonyl oxygen with the Cα at i − 4 on the opposing helix (vector 1-4), is approximately −35°.

Figure 4
(A) Connectivity of the networks of apparent Cα—H[center dot][center dot][center dot]O hydrogen bonds in the four parallel right-handed GpA-like motifs. The arrows show the interactions in the donor-to-acceptor direction. Black arrows: backbone-to-backbone ...

Among the four structures, the GpA dimer is the only one with GxxxG pairs present on both interacting helix surfaces (Fig. (Fig.44A). GxxxG was identified by Russ and Engelman (29) as a major motif driving oligomerization in a screen of randomized interaction interfaces. Furthermore, small residues spaced at i, i + 4 have increased occurrence in transmembrane helices; in particular, GxxxG is the most biased pair in transmembrane helices, being strongly over-represented in both single-span and multispan membrane proteins (28). Finally, several mutagenesis studies support the involvement of the GxxxG motif in transmembrane helix oligomerization and interaction (3035). In addition to favoring interhelical backbone contacts because of the lack of a side chain, Gly residues also increase the opportunities for Cα—H[center dot][center dot][center dot]O formation with two α-hydrogen atoms that can act as donors (denoted as 1Hα and 2Hα). In a helical conformation, the 2Hα of Gly (the hydrogen that is stereochemically in the position of the side chain in other amino acids) points in the same direction as the Hα of the residues at i + 1 and i − 3. Thus, in a GXxxG motif three Hα atoms (specifically, the 2Hα atoms of each Gly residue, and the Hα of the residue X at i + 1 with respect to the first Gly) are oriented roughly parallel and a potential interaction surface arises. This is illustrated in Fig. Fig.44C, where the Cα—H of Gly-79, Val-80, and Gly-83 of GpA are donors to carbonyl oxygen atoms on the opposite side spaced at i, i + 3 and i + 4. A similar pattern is also found in GlpF (donors Gly-243, Ala-244, and Gly-247). Hence, the present data suggest that the GxxxG motif drives transmembrane helix association in part by favoring Cα—H[center dot][center dot][center dot] O==C interactions. We have found GxxxG pairs only in parallel right-handed “GpA-like” interaction motifs, although numerous interfacial Gly residues occur in all identified interhelical networks with backbone-to-backbone contacts. It will be interesting to see whether the expectation of finding GxxxG pairs frequently—and perhaps mainly—occurring in GpA-like motifs will be met once more structural data become available.

Other Networks of Interhelical Cα—H[center dot][center dot][center dot]O Bonds.

Fig. Fig.55 shows four more examples of helix–helix interfaces with apparent Cα—H[center dot][center dot][center dot]O bonds: three very extensive networks (AC) containing several backbone-to-backbone Cα—H[center dot][center dot][center dot]O contacts occur in an antiparallel right-handed interaction (A, GlpF), a parallel left-handed interaction (B, cytochrome c oxidase), and an antiparallel left-handed interaction (C, photosynthetic reaction center). The interaction of Fig. Fig.55A is the third case found in GlpF. As with the other two interactions, it is right-handed and characterized by small interfacial amino acid residues spaced at i, i + 4 engaged in Cα—H[center dot][center dot][center dot]O contacts (AxxxGxxxS on helix 2 and GxxxA on helix 6), but it is antiparallel. An example from bacteriorhodopsin (bR) is shown in Fig. Fig.55D. The structure of bR has been solved at 1.55 Å and is currently the highest-resolution structure for a membrane protein. bR has interhelical distances in the range 7.8–10.6 Å, above the 7.6 Å that appears to be the approximate limit for backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C formation. However, backbone-to-side-chain Cα—H[center dot][center dot][center dot]O bonds are observed.

Figure 5
Additional helix–helix interactions with multiple Cα—H[center dot][center dot][center dot]O hydrogen bonds at various interhelical packing angles. (A) Antiparallel right-handed interaction from the GlpF. (B) Parallel left-handed interaction ...

It should be noted that the examples of Fig. Fig.55 do not have the thematic packing angles and connectivity seen in the right-handed parallel interactions. Instead, the central element characterizing all observed cases with backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C networks is the presence of numerous interfacial Gly, Ser, and Thr residues.

The Versatility of Glycine in Interhelical Cα—H[center dot][center dot][center dot]O Bond Networks.

Gly residues are frequent in transmembrane helices, constituting 8% of the amino acid composition (28). Gly residues permit short interhelical separation, and it has previously been suggested that they might participate in Cα—H[center dot][center dot][center dot]O bonds (36). In our analysis, 23% of all helical Gly residues appear to be involved as donors and 10% as acceptors in Cα—H[center dot][center dot][center dot]O contacts. As previously discussed, Gly residues increase the opportunity for Cα—H[center dot][center dot][center dot]O bond formation because the second Hα of glycine points roughly in the same direction as the Hα of the residues at i + 1 and i − 3 (Fig. (Fig.44C). In addition, both the Hα atoms of a Gly residue can simultaneously form Cα—H[center dot][center dot][center dot]O bonds to either different acceptors (Gly-83 in Fig. Fig.55B; Gly-244 in Fig. Fig.55C) or the same acceptor oxygen (bidentate interactions, Gly-184 in Fig. Fig.55A). Hence, the versatility of Gly residues appears to favor Cα—H[center dot][center dot][center dot]O network formation.

Serine and Threonine Allow Cα—H[center dot][center dot][center dot]Oγ Contacts at Longer Interhelical Distances.

Ser and Thr residues are frequently involved in interhelical Cα—H[center dot][center dot][center dot]O bonds. They each constitute 5% of the amino acid composition of transmembrane helices (28), where they are well tolerated because the donor potential of their polar side chains can be satisfied by forming O—H[center dot][center dot][center dot]O hydrogen bonds to the carbonyl at i − 4 or i − 3 on the same helix (37, 38). For this reason they have a weak tendency to form interhelical O—H[center dot][center dot][center dot]O hydrogen bonds (11, 13). The Oγ, however, is available as an acceptor and is displaced from the helix axis. In our database 24% of all Ser and 20% of all Thr residues appear to be involved in Cα—H[center dot][center dot][center dot]Oγ bonds. In particular, in GpA, Thr-87 allows the formation of an additional Cα—H[center dot][center dot][center dot]O when the interhelical distance is too large for the Cα—H of Val-84 to reach the backbone oxygen on the opposite helix (Fig. (Fig.33B). Consistently, the isosteric mutation of Thr-87 to Val results in partial destabilization of the GpA dimer (32). Moreover, the GxxxGxxxT motif was found by Russ and Engelman to be among the strongly associating helices in their selection of randomized interfaces (29) and the triplet is also strongly over-represented in transmembrane sequences (28). Thus, the frequent occurrence of Ser and Thr residues in transmembrane helices could be in part linked to their ability to engage in Cα—H[center dot][center dot][center dot]O hydrogen bonds.

Concluding Remarks.

By using known structures of helical membrane proteins, we have found common features in a number of helix–helix interfaces: (i) networks of apparent Cα—H[center dot][center dot][center dot]O bonds; (ii) abundant interfacial Gly, Ser, and Thr residues; and (iii) short interhelical axial distances. In particular, Gly residues permit backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C formation by allowing short interhelical axial distances; the two α-hydrogen atoms of Gly also increase the opportunities for Cα—H[center dot][center dot][center dot]O formation. Ser and Thr side-chain hydroxyl groups allow Cα—H[center dot][center dot][center dot]O interaction at longer interhelical distances. In addition, Cα—H[center dot][center dot][center dot]O contacts appear more frequently in parallel right-handed helix–helix interactions. Finally, right-handed parallel GpA-like motifs, in which GxxxG pairs promote extended Cα—H[center dot][center dot][center dot]O network formation, are a recurrent theme.

Cα and carbonyl O atoms are typically shielded by side chains in an α-helix, and so tend to be inaccessible. Derewenda et al. (14) defined C—H[center dot][center dot][center dot]O contacts between helices as “esoteric” in soluble proteins and, in fact, they did not report a single instance of helical Cα—H[center dot][center dot][center dot]O contacts with dH < 2.7 Å in 13 high-resolution structures (1–2 Å). Conversely, we have found 51 such contacts in 11 membrane proteins. Such a discrepancy is not due simply to the lower resolution of our database; instead, it depends on the frequency of Gly residues, which are rare in helical segments of soluble proteins but prevalent in transmembrane helices. It seems highly probable that Cα—H[center dot][center dot][center dot]O hydrogen bonds exist in helix–helix interfaces having numerous Gly residues, very short interaxial distances, and backbone contacts. Although Cα—H[center dot][center dot][center dot]O hydrogen bonding could be merely incidental to the optimal packing achieved with close-range interhelical contacts, the key is then the relative energy contribution of the Cα—H[center dot][center dot][center dot]O bond. If the estimate of 2.5–3.0 kcal/mol of interaction energy for the Cα—H[center dot][center dot][center dot]O hydrogen bond is even approximately correct, several coordinated interactions would approximate or even exceed the energy of the N—H[center dot][center dot][center dot]O hydrogen bond, which is known to drive nonspecific transmembrane helix association (1013). However, packing would still be central in helix–helix interactions promoted by coordinated Cα—H[center dot][center dot][center dot]O hydrogen bonds because main-chain atoms come in contact only between helices that fit together well. Moreover, because Cα—H[center dot][center dot][center dot]O hydrogen bonds are weaker than main-chain N—H[center dot][center dot][center dot]O==C, helix distortion would represent a substantial cost for their optimization. Thus, even if the energy contribution of backbone-to-backbone Cα—H[center dot][center dot][center dot]O==C interactions turned out to be overwhelming with respect to the dispersion component of packing, their formation would be much more dependent on the specifics of local geometry than that of O—H[center dot][center dot][center dot]O or N—H[center dot][center dot][center dot]O bonds between ends of flexible side chains, thus reducing the dangers of nonspecific association. The Cα—H[center dot][center dot][center dot]O could then be a more controllable and cooperative alternative to O—H[center dot][center dot][center dot]O or N—H[center dot][center dot][center dot]O bonds for exploiting the strength and directionality of hydrogen bonds in the hydrophobic environment and achieving, simultaneously, stability and specificity in transmembrane helix–helix interactions.

Acknowledgments

We thank J. Cabral, M. Cocco, R. Curran, J. Dawson, K. Ho, A. Lee, H. Li, M. Lemmon, N. Luscombe, K. MacKenzie, J.-L. Popot, J. Qian, B. Russ, and F. Zhou for helpful discussions and critical reading of the manuscript. This work was supported by grants from the National Institutes of Health and the National Science Foundation.

Abbreviations

GpA
glycophorin A
GlpF
glycerol facilitator

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