- Research article
- Open Access
Mirrors in the PDB: left-handed α-turns guide design with D-amino acids
© Annavarapu and Nanda; licensee BioMed Central Ltd. 2009
- Received: 24 April 2009
- Accepted: 22 September 2009
- Published: 22 September 2009
Incorporating variable amino acid stereochemistry in molecular design has the potential to improve existing protein stability and create new topologies inaccessible to homochiral molecules. The Protein Data Bank has been a reliable, rich source of information on molecular interactions and their role in protein stability and structure. D-amino acids rarely occur naturally, making it difficult to infer general rules for how they would be tolerated in proteins through an analysis of existing protein structures. However, protein elements containing short left-handed turns and helices turn out to contain useful information. Molecular mechanisms used in proteins to stabilize left-handed elements by L-amino acids are structurally enantiomeric to potential synthetic strategies for stabilizing right-handed elements with D-amino acids.
Propensities for amino acids to occur in contiguous αL helices correlate with published thermodynamic scales for incorporation of D-amino acids into αR helices. Two backbone rules for terminating a left-handed helix are found: an αR conformation is disfavored at the amino terminus, and a βR conformation is disfavored at the carboxy terminus. Helix capping sidechain-backbone interactions are found which are unique to αL helices including an elevated propensity for L-Asn, and L-Thr at the amino terminus and L-Gln, L-Thr and L-Ser at the carboxy terminus.
By examining left-handed α-turns containing L-amino acids, new interaction motifs for incorporating D-amino acids into right-handed α-helices are identified. These will provide a basis for de novo design of novel heterochiral protein folds.
- Backbone Amide
- Steric Clash
- Alanine Racemase
- Protein Data Base
- Amino Acid Propensity
Solid phase chemical synthesis allows for the incorporation of non-natural amino acids into polypeptides. The field has developed rapidly, permitting the construction of synthetic, protein-sized molecules. This has allowed protein chemists to explore the physical and biological effects of varying amino acid stereochemistry. A dramatic example was the chemical synthesis of the ninety-nine amino acid long HIV-1 protease from both L and D-amino acids. The resulting enantiomeric molecules were both well-folded and specifically active on a protease substrate of the same respective amino acid chirality as the enzyme. In this study, we use the Protein Data Base (PDB) as a source of structural information for specific D-amino acid sidechain interactions with α-helical backbones.
Much of the work on the role of variable stereochemistry on structure and stability has been conducted on short peptides [3, 4]. This work has been motivated by natural examples of polypeptides that combine L and D amino acids. The antimicrobial toxin, gramicidin, is a well studied example of such a molecule, containing alternating L and D amino acids. This allows it to adopt the β-helix, a novel secondary structure composed of alternating positions in the βL and βR conformation[5, 6]. The β-helix has been used as the foundation for novel cyclic peptide folds and peptide nanotubes with ion channel activity and antimicrobial properties [8–11]. Other microbial peptides such as tolaasin use D-amino acids to enforce sharp bends in an α-helical domain . Methods are being developed for incorporating L and D amino acids in computational de novo protein design [13–16].
Another practical application is the development of thermostable proteins that incorporate D-amino acids. Amino acids in proteins are rarely found in backbone conformations with positive φ and ψ angles at the αL region of Ramachandran space . This paucity of αL residues is primarily due to unfavorable interactions between the sidechain and its backbone carbonyl and that of the preceding residue. The energetic cost of this steric clash has been estimated at around 1 kcal/mole by replacing L-Ala with D-Ala in a model αR-helical peptide [18, 19]. The only amino acid that does not contribute this type of steric clash is Gly, which lacks a sidechain. Consequently, αL positions in proteins are primarily occupied by Gly [20, 21]. This feature of glycine has been applied to the thermostabilization of a bacterial formate dehydrogenase which has five non-glycine amino acids throughout the protein in the αL conformation. Replacing these amino acids with Gly increases the activity at otherwise inactivating temperatures.
The backbone amide of glycine makes hydrogen bonding with exposed carbonyls at the C-terminal end of a helix [23–26]. This allows the chain to maintain a network of stabilizing interactions while terminating the helix and changing the direction of the chain. Other amino acids besides glycine are sometimes found in such positions, but are rare due to steric constraints already mentioned. Small polar amino acids are commonly found at the N-terminus of an αR helix, making sidechain hydrogen bonds to exposed amides of the backbone [27–32]. Together, these interactions are called 'helix caps'.
D-amino acids can function as C-terminal helix caps. While substitution of αL positions with Gly may remove unfavorable contacts, the entropic cost of fixing glycine in a given conformation can mitigate energetic benefits gained. D-amino acids, which favor the αL conformation, have been substituted for Gly, sometimes resulting in increased protein stability [33–35]. Observed folding free energy changes have ranged from zero to over two kcals/mol. In a monomeric helical peptide, adding D-Ala to the C-terminus of a helix resulted in no significant change in stability whereas D-Arg increased stability by approximately one kcal/mole, presumably due to stabilization of the helix macrodipole . These varying results indicate that the roles of sidechain identity and stereochemistry in protein stability are still an open problem.
While much has been learned about standard capping interactions from the analysis of high-resolution protein structures in the PDB, the number of proteins containing D-amino acids is very low. Approximately 150 entries in the PDB contain D-amino acids that are not artifactual, and most of these are shorter than twenty amino acids. A handful of these contain D-amino acids in helix C-capping contexts [1, 34]. A number of designed heterochiral peptides are in the Cambridge Structural Database (CSD) of small molecules, but these are of limited use for the unbiased discovery of novel capping interactions.
One possible source of information is a set of small, contiguous left-handed turns and helices in proteins. These are rare due to the unfavorable steric interactions required to place L-amino acids in the αL conformation. For cases where such structures do exist, they often play key structural and functional roles . Stabilizing interactions identified in a study of naturally occurring left-handed structures would be perpetrated by L-amino acids. Hence, the value to protein engineering and design is to realize that the structural enantiomer of such interactions would involve right-handed structures stabilized with D-amino acids.
This report outlines the search of a non-redundant subset of the PDB for left-handed turns and short αL helices. The total fraction of amino acids in the αL conformation is 4%, over half of which is attributed to glycine . Despite this, a small set of left handed structures are identified for structural analysis. The intrinsic αL-helical preferences of most amino acids correlate with thermodynamic scales for inserting D-amino acids into αR helices. Furthermore, several N- and C-terminal capping motifs unique to left-handed helices are described. These are tantalizing candidates for novel D-amino acid capping motifs of αR-helices. Implications for protein stabilization and heterochiral protein design are discussed.
Backbone Geometry in Left-handed Turns and Helices
A non-redundant subset of structures in the PDB was searched for three or more contiguous residues in an αL conformation. Seventy-two three-residue turns, ten four-residue helices and two five-residue helices were found (see Additional Files 1, Table S1). In order to keep nomenclature consistent with previous studies , the relative positions of amino acids within these turns and helices are described as follows: the Ncap residue is the first amino acid in a contiguous left-handed conformation; the Ccap residue is the last amino acid in a contiguous left-handed conformation. The remaining positions are described in their position relative to the Ncap or Ccap:
In three residue turns, N1 = C1.
Amino Acid Preferences in Left-handed Structures
Mean amino acid propensities in three-residue left-handed turns and flanking positions.a
The highest propensities at the N1 - N3 positions belong to Gly and L-Asn. L-Asp is highly represented at the Ncap and N1 positions. These are also the three amino acids with the highest individual αL propensity in the database. The preference of L-Asn (and L-Asp) for the αL has been suggested to result from favorable dipole-dipole interactions of sidechain and backbone carbonyls. β-branched amino acids, L-Ile, L-Val and L-Thr are highly unfavorable. L-Pro is clearly not found in these structures due to the restriction of φ ≈ -60° by the cyclic sidechain.
Log propensities and thermodynamic scales of helix formation
Correlations of log-propensities and thermodynamic scales
I, T, Va
W, F, Ya
I, T, V, W, F, Ya
-ln(PαL-helix) vs. D-scale
-ln(PαL-not helix) vs. D-scale
-ln(PαR-helix) vs. L-scale
-ln(PαR-not helix) vs. L-scale
L-scale vs D-scale
This strong correlation between database and experimental values is surprising, given the comparison of three-residue turns to the much longer eighteen-residue α-helix used in the host-guest studies. In an a-helix, an amino acid sidechain will often interact with i-3 and i-4 positions, either directly through van der Waals packing or hydrogen bonding, or indirectly through shielding of solvent interactions. It is possible that the host-guest scale is dominated by local stereochemical effects, rather than interactions with nearby residues that could have a cooperative effect on folding. To test this, a different set of database propensities were calculated using amino acids in an αL conformation where preceding and following amino acids were not αL. In this case, the correlation with the Krause scale also improves (R = 0.79 Figure 2B). This suggests that the experimental D-scale is describing the propensities of amino acids to assume backbone φ and ψ angles relating to an αR conformation, rather than reporting on steric interactions with i-3, i-4 positions in a helical context. Because monomeric helix folding-unfolding is not a two-state process [44, 45], the amphipathic monomeric helix used may not reflect thermodynamic contributions in a larger protein where helix folding is coupled with assembly of other structural elements.
The amino acid with the lowest stability in αR helices is L-His . Conversely D-His is one of the least destabilizing amino acids in αR helices . L-His is observed with elevated frequency at the N1 position in this study. Assuming the neutral imidazole tautomer where Nδ1 is deprotonated, histidine is the only other amino acid beside Asn and Asp that presents a lone pair separated by three bonds from the Cα carbon on the backbone. If the dipole-dipole interaction between backbone and sidechain carbonyls suggested for L-Asp and L-Asn  can stabilize the αL conformation, one may speculate that a similar mechanism may be at work in the case of the imidazole Nδ1 lone pair and its dipolar interaction with the backbone carbonyl.
Backbone Conformations for Positions Flanking a Left-handed Turn
At N', the αR conformation is disallowed. When a helix is modeled with an αR residue followed by an αL helix, no strong steric clash is observed (Figure 6). However, the Cβ sidechain methyl of the N' residue prevents solvation of the N2 backbone amide. Desolvation of polar groups are energetically unfavorable when no intrinsic hydrogen bond within the protein replaces the interaction. This desolvation penalty can be partially relieved by placing the N' in either the βR, PPII or γR conformation. Thus, two conformational rules unique to flanking positions of left-handed helices emerge: αR-(αL)n and (αL)n-βR are disfavored where n ≥ 3. Similar rules would apply to the structural enantiomer where D-amino acids precede or follow an αR helix: αL-(αR)n and (αR)n-βL would be disfavored for n ≥ 3.
Sidechain-Backbone Interactions at the N-terminus
If the N' residue is in the βR conformation as pictured in Figure 6B, unfavorable desolvation of the N2 amide is avoided, but the N' sidechain projects away from the top of the helix, preventing any specific polar capping interactions with the N-terminal amides. Such capping interactions are prevalent in αR helices which often feature L-Thr, L-Asn or L-Asp at the N-terminus making sidechain oxygen acceptor hydrogen bonds to exposed backbone amides[27, 28]. To accommodate this, the capping residue is usually in the β conformation. A similar propensity for small polar amino acids at the N' is observed in our database of left-handed turns. However, for these to facilitate sidechain-backbone capping hydrogen bonds while avoiding desolvation of N2, the residue must be in the γR (ψ > 0°) conformation. Although both αR and αL N-terminal capping interactions involve small polar amino acids, the interactions presented here are structurally distinct from those previously identified
In a designed turn-helix peptide, a D-Asp was utilized to contribute similar interactions at the N-terminus of an αR helix (Figure 7C) . These N-terminal interactions are a subset of a larger class of motifs in proteins and peptides described by Milner-White and colleagues as peptide 'nests' [30, 52]. These nests often serve as anion binding sites, complexing both sidechains and prosthetic groups such as phosphates and iron-sulfur clusters [53, 54].
Sidechain-Backbone Interactions at the C-terminus
It is interesting to compare our observations with studies on the energetics of C-terminus helix capping through chemical synthesis of proteins with D-amino acids. Bang and coworkers replaced Gly 35 of ubiquitin, which sits in the αL conformation at the end of an αR helix, with D-Ala, D-Gln, D-Val and D-Thr. D-Ala and D-Gln have comparable stabilities and are both very close to the stability of the wild type Gly 35 protein. The β-branched amino acids are less stable by nearly 1 kcal/mol. D-Val is less stable than D-Thr by approximately 0.5 kcals/mol. Although the study states that these energy differences relative to glycine correlate with changes in solvation of the carboxy terminus, it is possible that specific interactions such as the ones we observe are also contributing to capping energetics. This would explain the increased stability of D-Thr over D-Val, which has the facility to form Ccap hydrogen bonds in the αL conformation to an αR helix. The similarity in energetics of D-Gln and D-Ala show that in ubiquitin, D-Gln sidechain capping interactions are not playing a significant role in protein stabilization. In high resolution structures of the D-Gln 35 mutant, the sidechain does not make the same capping interaction we observe, but rather is involved in quaternary contacts with other ubiquitins in the asymmetric unit[1, 34]. With three rotameric degrees of freedom, Gln has to pay a higher entropic cost to form the specific hydrogen bond to the C2 carbonyl. This may cancel the energy gained by forming a capping hydrogen bond. We have recently shown that Gly to D-Gln mutations can significantly increase the stability relative to the D-Ala substitution of the Trp-Cage. (manuscript in preparation).
Stabilization Through Tertiary Interactions
The PERL script used to identify αL regions is included as Additional Files 2: findalphaleft.pl
To make the rational engineering and design of heterochiral proteins tractable, the role of amino acid stereochemistry in stability and structure needs to be better understood. This study presents potential rules based on insights gained from the analysis of natural proteins. Using left-handed turns and helices in the database of existing protein structures as a case study, we have found several candidates for motifs that could be applied to the thermostabilization of proteins by synthetic amino acids. As synthetic methods for building proteins continue to improve, the ability to construct larger molecules with mixtures of natural and synthetic amino acids becomes increasingly practical. Natural proteins can provide important insight into how designed proteins can take advantage of the increased chemical diversity made possible by synthetic methods.
Compiling a non-redundant set of PDB files
A list of non-redundant protein chains was assembled using PISCES http://dunbrack.fccc.edu/[60, 61]. Structures obtained through X-ray crystallography with a resolution greater than 2.5 Å and sequence homology less than 25% were included. The final database consisted of 3517 unique chains.
Searching for αL helices
PERL scripts were constructed to search each file on the non redundant list for presence of αL helices of three residues or longer (see Additional Files 2). φ and ψ values were computed based on deposited backbone coordinates of the N, C, Cα and O atoms (see scripts for details). φ values between 35.0° and 95.0° and ψ values between 10.0° and 70.0° were classified as αL. Allowable ranges were settled on after starting with more generous ranges and narrowing the window until all structures showed i, i+3 and or i, i+4 hydrogen bonding (determined geometrically by checking the backbone N to O distance was less than or equal to 3.5Å). Initially, the search returned eighty-five αL-helices and turns of which seventy-three were three residues long, ten were four residues long and two were five residues long.
In order to assess local structure quality, backbone B-factors were examined for the three-residue α-turns in our data set. Three turns in our data set with B-factors greater than one standard deviation from the mean were flagged for manual examination. WinCoot was used to visualize electron density maps based on structure factors deposited at the EDS. One structure for which there was poor electron density in the turn region was removed from the data set (see Additional Files 1: Figure S1).
Calculating amino acid propensities
Sequences of the three residue left-handed turns were analyzed to determine amino acid propensities at each position in the turn. The occurrence of an amino acid at each position was divided by occurrence in the PDB dataset to obtain normalized values.
The propensity for a particular amino acid to occur in the Ncap, N1 or Ccap position was compared to the overall frequency of that amino acid type in the αL conformation in any context. Overall frequencies were calculated using the same data set of proteins from which the left handed turns were selected.
We thank Joe Marcotrigiano for help with electron density map visualization, Peter Lobel for useful discussions and the UMDNJ Foundation for support of SA.
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