PEDS Advance Access originally published online on June 24, 2006
Protein Engineering Design and Selection 2006 19(9):401-408; doi:10.1093/protein/gzl024
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Designing amino acid residues with single-conformations
1 Ludwig Institute for Cancer Research and Cooperative Research Centre for Cellular and Growth Factors, Melbourne Victoria 3050, Australia
2To whom correspondence should be addressed. E-mail: Tony.Burgess{at}ludwig.edu.au
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Abstract |
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Drug design can benefit from the use of non-coded amino acids, such as
-amino isobutyric acids (Aib) or sarcosine (N-methyl-glycine). Non-coded amino acids can confer resistance to enzymatic degradation and increase the conformational stability of the peptides. We have simulated the conformational effects of combining N-methylation, bulky groups on the C atom and/or thioamides using the class II CFF91 force field and our thioamide force field parameters. Although single amino acid substitutions (e.g. Aib) can restrict the available conformations, they do not necessarily lead to unique conformers, however, we predict that some of the amino acids described in this report will fold to a single 
, 
conformation (e.g. N-methylated and thioamide penicillamine). Several other amino acid/thiopeptide combinations were designed, which are predicted to prefer only two conformations. Novel amino acids of this type should prove useful for designing peptides with defined conformations.
Keywords: conformationally restricted amino acids/N-methylation/penicillamine/protein engineering/thioamide
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Although a large number of chemically and conformationally diverse peptides and proteins can be produced through different combinations of the 20 natural amino acids encoded by DNA, the introduction of non-coded amino acids, such as
-amino isobutyric acid (Aib) (Aubury et al., 1978
; Paterson et al., 1981; Prasad et al., 1984) or sarcosine (N-methyl-glycine) can enhance the diversity of synthetic peptides for drug discovery. Apart from the increased diversity, non-coded amino acids, or terminal blocking groups (Vasquez et al., 1983), have been utilized in many ways: (i) to confer resistance to enzymatic degradation (Mock et al., 1981; Spatola, 1983; Michel et al., 1989), (ii) to probe the function of particular residues in protein structures (Turk et al., 1975; Juvvadi et al., 1992; Rutledge et al., 1996), (iii) for the process of de novo peptide design (Marshall and Bosshard, 1972; Burgess et al., 1973; Prasad et al., 1984; DeGrado et al., 1991; Karle et al., 1991; Ramnarayan et al., 1995), (iv) for the design of structures with novel folds or secondary structures (Appella et al., 1996; Seebach et al., 1996; Che et al., 2006; Salaun et al., 2006), (v) to create new combinatorial chemistry libraries (Simon et al., 1992; Kessler, 1993; Zuckermann et al., 1992, 1994; Miller et al., 1995; Allinger et al., 1996) and (vi) to be used in de novo drug design where a specific fit to a target surface is required (Veber et al., 1979, 1981).
Novel amino acids often introduce extra substituents on the peptide backbone: the amide nitrogen, the -carbon or the C'. The effects of single additions or substitutions at these three positions have been reported by others (Manavalan and Momany, 1980; Spatola, 1983; Burgess, 1994; Mohle et al., 1995; Sewald et al., 1995; Koksch et al., 1997; Valle et al., 1988, 1989, 1991). We have previously derived force field parameters for thioamides (Tran et al., 2001a,b,c,d, 2002), which enable studies on the conformational and hydrogen bonding effects of substituting S for O at the peptide carbonyl group. The aim of this paper is to discover/design non-coded amino acids that have single conformational states at particular positions. This can be achieved by combining thioamide substitution, N-methylation and addition of bulky group onto the C atom.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The conformational energy (
, ) maps for the N-acetyl-N'-methyl amino acid amides were obtained by minimization with torsion forcing at every 10° or 15° increment of the and dihedral angles using the discover program of MSI, the CFF91 (Hwang et al., 1994; Maple et al., 1994) force field (Maple et al., 1994) and our previously derived thioamide force field parameters (Tran et al., 2001a,b,c,d). Energy minimizations were performed using the artificial torsion forcing function 4444[1 – cos(V – V0) Discover Force-Field Manual (1995), www.accelrys.com], convergence criteria of 0.01 kcal/mol, no non-bonded cut-off, and a dielectric constant of 80 (Tran et al., 2001c). For dipeptides containing the penicillamine modification, the 
torsional angles were searched systematically to ensure the appropriate positioning of the large side chain for each , conformer.
To identify amino acid/peptide combinations which favor a single conformer, we determined all of the energy minima on the (, ) conformational energy map and identified conformational minima within 2.0 kcal/mol of the global minimum, which were separated from the other minima by an energy barrier greater than kT (0.6 kcal/mol).
Almost 40 years ago, Ramakrishnan and Ramachandran (1965) predicted the favorable areas of the (, ) surface for glycine and alanine dipeptides using a classical hard sphere model and Mandel et al. (1977) used the ‘Derivation diagram’ to explain the steric contacts at each point on the , surface. We have used similar diagrams to describe the pairwise interactions influencing the conformational stability in particular regions of the (, ) energy maps. As the dihedral angle of Ac-Ala-NHMe is rotated, the On–1 and the Hn atoms interact with three major atoms or groups of atoms, Cß, Hß and Pn, where Pn is defined as the four atoms in the peptide, Cn, On, Nn+1 and Hn+1. When the dihedral angle is rotated, the Hn+1 and the On atoms interact with Cß, Hß and Pn–1, where Pn–1 is defined as the peptide group containing the four atoms, Nn, Hn, Cn–1 and On–1. These interactions are displayed on the conventional (, ) energy maps in Figure 2.
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Results |
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We have attempted to restrict the conformations of non-coded amino acid dipeptides by introducing either single modifications to the amino acid residue or to the peptide bonds or by combinations of these substitutions (Figure 1). In particular, we have simulated the effects of replacing the Hn atom with a methyl group for dipeptides and thiopeptides. We have also explored the effects of replacing the Hß with small substituents and the influence of more bulky Cß substituents.
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The (
, ) energy maps (Figures 2–5) indicate the conformational preferences for the substituted amino acid or peptide modifications described in Figure 1. The energy maps are annotated to illustrate the atoms which interact strongly at particular regions on the conformational energy surface.
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Interactions between N-methylation and thioamide substitution of the peptide backbone
N-methylation of either or both of the peptide bonds [Ac-NMeAla-NHMe, Ac-Ala-NMe2, Ac-NMeAla-NMe2, Ac(cis)-NMeAla-NHMe and Ac(cis)-NMeAla-NMe2, Figure 1) restricts the conformations available to the dipeptides. The relative energies of the favorable , minima and the percentage of the , energy surface within 2 kcal/mol of the global minimum are summarized in Table 1. For conciseness, only the , maps that are predicted to lead to interesting conformational restrictions are presented in Figures 2–5. The results for the other dipeptides listed in Figure 1 are available on our web page [Designing single conformation amino acids, Tran (2006), www.ludwig.edu.au/archive/tran]. N-methylation of the N-terminal peptide bond [Ac-NMeAla-NHMe] potentially increases steric hindrance causes by interactions between groups at = –180°, –60°, 60° and 180° and at = 180°, 0° and –180°. However, only the eclipses near the = 180° or –180° and = 180° or –180° regions lead to significant energy increases on the (, ) surface (Figure 2).
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N-methylation of the C-terminal peptide bond, [Ac-Ala-NMe2] (Figure 2), leads to unfavorable interactions near
= –120° and = 0° (see Figure 2). Consequently, the R region is no longer favored, leaving two favorable minima in the ß-sheet (–75° and 150°) and L (60° and 75°) regions.
Thio substitutions at both peptide bonds of Ac-Ala-NMe2 disfavor the L region and the C5 regions, leaving the ß-sheet (–60° and 135°) conformation as the only conformation likely to be favored by the Act-Alat-NMe2 (Figure 2). All the other local minima are predicted to be more than 2 kcal/mol higher in energy.
The effects of double N-methylation at both the C- and N-terminus of alanine dipeptides are similar to the combined effects of the two single N- and N'-methylations. The < 0 and the C5 regions are disfavored, leaving three favorable minima, ß-sheet (–70°, 150°), L (60°, 60°) and the (–120°, 75°) regions (Figure 2 and Table 1). It was thought that thio substitutions might introduce a high-energy region at = 60 and therefore block the two favorable minima at (–120°, 75°) and L (60°, 60°) regions. However, thio substitutions only interfere with the L minimum, leaving two favorable minima remain in the ß-sheets regions: (–75°, 135°) and (–135°, 75°) (see Act-NMeAlat-NMe2 in Figure 2).
Effects of substitution at the position on the conformations of peptides and thiopeptides
The (, ) conformational energy map for Act-Aib-NHMe is similar to that of Ac-Aib-NHMe with six conformational energy minima at: (60°, 45°), (–60°, –45°), (180°, 75°), (180°, –75°), (–60°, 165°) and (60°, –165°) (Figure 3 and Table 1). A search in the Cambridge Structural Database (Allen et al., 1993) resulted in the Boc-Gly-Alat-Aib-OMe (Jensen et al., 1985) as the only X-ray crystallographic structure containing thio-peptide at the N-terminal of Aib. The (, ) dihedral angle for the Aib residue in Boc-Gly-Alat-Aib-OMe is (53°, 42°), which is close to the global minimum (60°, 45°) of the calculated (, ) map for Act-Aib-NHMe.
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The conformations available to Ac-Aibt-NHMe and Act-Aibt-NHMe are more restricted with the locations of favorable minima at (60°, –135°), (–60°, 135°), (60°, 30°) and (–60°, –30°). Compared to the Aib dipeptide map, the region near
= –60 and = 60 regions for the thiopeptides are less favorable, most likely as a result of the increase in steric hindrance between Sn and Cß and between Sn and Cß, respectively. This increased steric hindrance shifts the global minimum from the -helical regions to the ß-sheet region. The second favored conformer shifts from the -helical minima (60°, 60°) and (–60°, –60°) to the 310-helical region (60°, 30°) and (–60°, –30°). Effects of bulkier side chains on the conformations available to peptides and thiopeptides
The (, ) conformational energy maps for Ac-Ala-NHMe and Ac-Aib-NHMe show that the eclipse between On–1 atom and Cß methyl group effectively excludes conformations near = 120. However, the overlap between On atom and Cß methyl groups does not exclude conformations near = 60. It is reasonable to hypothesize that a group larger than the methyl group at the ß position may make these eclipsed regions less favorable. We examined the conformational effects of introducing three such groups Ac-Afa-NHMe(aryl Cß), Ac-Tfa-NHMe(triofluoro Cß) and Ac-Pen-NHMe [Figures 1, 4 and 5, and our web page (Tran, 2006, www.ludwig.edu.au/archive/tran)]. Only the (, ) conformation energy map for Ac-Pen-NHMe is discussed in this report as it is predicted to exhibit the most severe conformational restriction.
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When compared to the (
, ) map for Ac-Ala-NHMe, the (, ) map for Ac-Pen-NHMe shows the bulky-CMe2SH group leads to three additional high-energy regions near = 120°, = –120° and = 60°, which correspond to the eclipses of On–1 Pen, On Pen and Hn+1 Pen, respectively. Consequently, the conformation of the Ac-Pen-NHMe dipeptide is predicted to be restricted to the three favorable minima, ß (–135°, 105°), R (–75°, –60°) and perhaps L (60°, 75°). When the peptide bond is thio substituted, forming Act-Pen-NHMe, Ac-Pent-NHMe and Act-Pent-NHMe, there is increased steric hindrance between the S atom and the ‘Pen’ group in the = 120° region for the N-terminal substitution and the = 60° region for the C-terminal substitution (Figure 4 and Table 1). This effectively disfavors the L (60°, 75°) energy minimum. Single conformations predicted for N-methylated forms of Aib peptides
The combination of N-methylation of the N-terminal peptide and Aib [Ac-NMeAib-NHMe] (Figures 1 and 3) leads to four favorable minima: R (–45, –60), L (45, 60), ß-sheet (–45, 135) and ß'-sheet (45, –135) (Table 1 and Figure 3). N-methylation of the C-terminal peptide of Aib produced the unusual (, ) map shown in Figure 3. This (, ) map shows two favorable minima in the R (–60, –60) and L (60, 45) regions and two unique favorable minima at (–180, 75) and (165, –60). The increased steric hindrance between the N-methyl group and the methyl groups attached to the C atom near = 120 or –120 destabilizes the (–60, 165) and the (60, –165) energy minima associated with Ac-Aib-NHMe. If both peptide bonds of the Aib dipeptide were N-methylated, [Ac-NMeAib-NMe2] only one favorable minima R (–45, –60) is likely to form (Figure 3 and Table 1).
Single conformation is predicted for the N-methylated and thioamide substituted penicillamine dipeptide
The (, ) conformational energy maps for the different combination of N-methylation and thio substitution of the penicillamine dipeptide are shown in Figure 5. N-methylation of the penicillamine dipeptides leads to global minima near the parallel ß-sheet region (–125°, 90°). Ac-NMePen-NHMe and Ac-NMePen-NMe2 also have an additional favorable minimum at the L region. Thio substitution of Ac-Pen-NMe2 is expected to change the single favorable minimum for Ac-Pen-NMe2 from (–135°, 105°) to (–75°, 120°) (see Act-Pent-NMe2 in Figure 5). The change in conformation is a consequence of higher steric hindrance between the Sn atom and the bulky-CMe2SH group near = 60°. When thio substitutions are introduced to Ac-NMePen-NMe2, the higher steric hindrance between the Sn atom and the bulky-CMe2SH group near = 60° destabilizes the L minimum and consequently, a single favorable minimum is seen at ß-sheet (–120°, 90°) region. The restricted conformations available to these peptides suggested that strong conformational preferences could be build into Pen peptides by manipulating the adjacent peptide bonds with by N-methylation and/or thio substitutions.
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Discussion |
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The CFF91 force field used in the calculations of (
, ) conformational energy maps was not derived directly for the non-coded amino acids explored in this study. Nonetheless, the agreement between the calculated (, ) maps and the experimental results for some of these non-coded amino acids indicates that the parameters are reasonable for the prediction of the conformations and approximate relative energies of minima for these peptides containing these non-coded amino acids.
For example N-methylation of the N-terminal peptide bond results in a (, ) map which shows two favorable minima near L (60°, 60°) and C7equatorial (–120°, 75°). The equivalent (, ) maps by previous authors (Marshall and Bosshard, 1972; Tonelli, 1976; Marshall et al., 1977; Manavalan and Momany, 1980) using simpler force-fields (rigid bond lengths and angles) also predict minima near the L and C7equatorial regions and a destabilization of the C5 region. However, the energy minima in the maps calculated by Tonelli (1976) and Manavalan and Momany (1980) are more restricted in the extended region. The experimentally observed conformations for Ac-NMeAla-NHMe, plotted on our (, ) maps as open dots (Figure 2), are within 2.5 kcal/mol of the global minimum, confirming the predictive value of our force field calculations.
The predictions of the effects of N-methylating the C-terminal peptide bond are very similar to that of Marshall and Bosshard (1972), Tonelli (1976) and Manavalan and Momany (1980) excepting that the forcefields with fixed bond lengths and angles lead to more restricted conformations. Our predictions for the effects of methylating both peptide bonds are very similar to that of Manavalan and Momany (1980) except for the steeper energy minima in their maps.
The (, ) map for Ac-Aib-NHMe calculated in this study were similar to the (, ) maps by previous authors (Marshall and Bosshard, 1972; Burgess et al., 1973; Prasad et al., 1984; Ramnarayan et al., 1995) and is consistent the experimental (, ) distribution for Aib (Uma et al., 1991) [i.e. mostly in the R and L regions and some near the ß-sheet (–60°, 165°) and ß'-sheet (60°, –165°) regions]. No conformers have been observed in the low energy regions (180°, –75°) and (180°, 75°). A possible explanation is that the helical conformations of Aib observed experimentally in peptides and proteins are often stabilized by the long range interaction such as i
i+3 or ii+4 intramolecular hydrogen bonds. Comparing the (, ) maps for Ac-Ala-NHMe (Figure 2) and Ac-Ala24-NHMe (Hobohm et al., 1992), the (180°, –75°) region and (–180°, 75°) region appears to be disfavored relative to the helical regions upon polypeptide consideration (Tran et al., 2001b). Paterson et al. (1981) calculated the (, ) maps for Ac-Aibn-NHMe with n = 1, 2 or 3 and concluded that as n increases, the (180°, –75°) and (–180°, 75°) regions are disfavored relative to the -helical region.
Concerning the effects of thiolation of Aib peptide bonds (Balaji et al., 1990) investigated the energies of Act-Aibt-NHMe using the MM2 force field and they also found the shift of the global minimum from the helical region ±(50°, 40°) to the ß-sheet region ±(–60°, 140°). However, they did not report the likely shift of the -helical region to the 310-helical region upon thio substitution.
The and values for L-Pen, determined from the experimentally derived structure of [D-Pen2,D-Pen5]Enkephalin analogs (Hruby et al., 1988; Flippenanderson et al., 1994; Collins et al., 1996) are shown on the (, ) map of Ac-Pen-NHMe in Figure 4. All of these conformations are within 2 kcal/mol of the global minimum except for the (75°, 15°) conformation, which is 3.5 kcal/mol above the global minimum. However, the dihedral angle of D-Pen2 is restricted by the disulfide bond between D-Pen2,D-Pen5, so further experimental determination of the conformation of free penicillamine residue is required to clarify whether the discrepancy between the calculated and the observed stability near the (75°, 15°) conformation is caused by a limitation of the CFF91 force field or the disulphide constrained dihedral angle. Nevertheless, the closeness of the other experimentally observed conformations to our global minimum is an indication that our calculation of the restricted conformational energy surface for Ac-Pen-NHMe based on the CFF91 force field is predictive of the conformational properties of this unusual side-chain.
Although, the single modifications of dipeptides are predicted to restrict the conformations available to peptides, none of these single substitutions would appear to be capable of restricting the conformations of a peptide to a single (, ) region . However, by combining some of these modifications, we predict that single favorable conformation states can be forced on the dipeptides. For some of the modified dipeptides, <4% of 3.6% of the (, ) conformational space is within 2 kcal of the global minimum. Although, we report the minima within 2 kcal of the global minimum, other energy minima up to 5 kcal are reported on the confrontational energy maps. In general, we have reported all of the likely conformations for the different peptides. By considering further combinations of substitutions and/or chirality at the C atom, the design process leads directly to other amino acids that will direct the fold to different regions of the (, ) maps. Further calculations on these conformationally restricted amino acids in a polypeptide environment should reveal how these substitutions affect the standard secondary structures and/or reveal novel polypeptide secondary structures.
All the singly substituted amino acids in this report have already been synthesized and incorporated into peptides. To our knowledge, the amino acids formed by the combination of N-methylation, additions at the C with ‘Aib’ or ‘Pen’ and thio substitutions have yet to be synthesized. Although steric clashes can hinder the synthesis of some of these amino acids, no particular problems are expected for the remaining amino acids because they are composed of combinations of substituents that have been used in peptide synthesis for many years.
Although, Aib has four favorable minima, it has proved to be a useful conformational determinant. The amino acids designed here, which are even more conformationally restricted, should also prove to be useful peptide building blocks.
The iso-energy contours on the (, ) conformational energy maps are 1 kcal/mol apart starting from the global minimum, which is marked with the yellow colored letter ‘X’. The black letter ‘X’ marks the minima that are within 2 kcal/mol from the global minimum and ‘0’ marks experimental conformation. The green and red shades in the maps represent low- and high-energy region, respectively. Labels for the eclipses of the interacting atoms or groups are shown on the top and the right of the (, ) maps. The labels are printed in boldface and underlined to highlight the eclipses that potentially lead to higher energy conformations. Sparsely dotted and closely dotted black lines are drawn on the maps to illustrate the eclipses that lead to high-energy regions for Ac-Gly-NHMe and Ac-Ala-NHMe, respectively. Sparsely dotted blue lines illustrate the high-energy eclipsed region associated with single modification. Closely dotted blue lines highlight the high-energy eclipsed region associated with interactions between the modification groups.
Eclipses, i.e. the atom pairs forming the shortest distances in particular regions are labeled on the top and the right side of the (, ) maps. For example, the glycine dipeptide in Figure 2 reports that the eclipse between On–1 and Pn occurs near = 0 and the eclipse between Hn+1 and Pn–1 is near = 0°. These interactions are responsible for significant increases in the energy at these regions. The Cß methyl group in the alanine dipeptide leads to four additional eclipses: (i) between Hn and Cß at = –60°, (ii) between On–1 and Cß at = 120°, (iii) between On and Cß at = 60° and (iv) between Hn+1 and Cß at = –120°. The labels for these four additional eclipses are printed in boldface and underlined.
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Footnotes |
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Edited by Harold Scheraga
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Received January 19, 2006; revised May 17, 2006; accepted May 30, 2006.
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