ORIGINAL PAPER

The preferred conformation of dipeptides in the contextof biosynthesis

Robert P. Bywater & Valera Veryazov

Received: 7 May 2013 /Revised: 18 July 2013 /Accepted: 20 July 2013 /Published online: 13 August 2013# Springer-Verlag Berlin Heidelberg 2013

Abstract Globular proteins are folded polypeptide structurescomprising stretches of secondary structures (helical (α- or310 helix type), polyproline helix orβ-strands) interspersed byregions of less well-ordered structure (“random coil”). Proteinfold prediction is a very active field impacting inte alia onprotein engineering and misfolding studies. Apart from themany studies of protein refolding from the denatured state,there has been considerable interest in studying the initialformation of peptides during biosynthesis, when there are atthe outset only a few residues in the emerging polypeptide.Although there have been many studies employing quantumchemical methods of the conformation of dipeptides, thesehave mostly been carried out in the gas phase or simulatedwater. None of these conditions really apply in the interiorconfines of the ribosome. In the present work, we areconcerned with the conformation of dipeptides in this lowdielectric environment. Furthermore, only the residue typesglycine and alanine have been studied by previous authors,but we extend this repertoire to include leucine and isoleu-cine, position isomers which have very different structuralpropensities.

Keywords Dipeptides . Biosynthesis . Proteins

Introduction

The problem of calculating peptide conformation has attractedattention from many authors who have resorted to quantummethods to calculate what would be the most stable confor-mations of peptides.

For the simplest case, structures based on N-acetyl-(Gly)(2)-N′-methylamine ((S)-α-(acetylylamino)-ethanamide) representinga primitive glycine dipeptide (GD) and N-acetyl-(Ala)(2)-N′-me-thylamine ((S)-α-(acetylylamino)-propanamide) representing aprimitive alanine dipeptide (AD) have been studied byseveral authors (Cheam and Krimm 1989; Gould et al 1994;Wu et al 2010). In one example (Gould et al 1994), GD andAD were studied at the HF/6-31G** level in gas phase andsimulated solvent conditions. These authors found multipleminima which corresponded in one way or another to earlierproposed minimum energy conformations of peptides (Liljaset al 2009), in particular, corresponding to the α- or 310 helixtypes. This was in contrast to later work (Wu et al. 2010) onAD using geometry optimization and single-point energycalculations at the B3LYP/cc-pVTZ//B3LYP/6-31G* level.These authors found that the most stable conformation wasthat having torsion angles corresponding to the β-strand,while that characteristic of α-helix had 13.6 kcal/mol higherfree energy. Earlier work (Cheam and Krimm 1989) foundminima for AD at sites corresponding to the polyproline helixand at two other locations; neither of which corresponded toany of the canonical secondary structure conformations (Liljaset al 2009).

There is clearly an issue to be resolved here. In order toclarify this issue, we studied, alongside AD and GD, thecorresponding primitive dipeptides based on leucine (LD)and isoleucine (ID). This is because leucine is known tofavour α-helix while isoleucine tends to avoid that conforma-tion (Bellesia et al 2010; Hovmoller et al 2002; Bywater et al2001) (except in membrane proteins (Bywater et al 2001)).

Communicated by: Sven Thatje

R. P. Bywater (*)Magdalen College, High Street, Oxford OX1 4AU, UKe-mail: romeobravo@adelard.org.uk

V. VeryazovDepartment of Theoretical Chemistry, Lund University,POB 124, Lund 22100, Swedene-mail: valera.veryazov@teokem.lu.se

Naturwissenschaften (2013) 100:853–859DOI 10.1007/s00114-013-1085-7

In addition to our interest in the conformation of the prim-itive dipeptides, we wished to explore the question: what isthe energetically most favoured conformation of theincipient dipeptide which is formed in the ribosome as thepeptidyltransferase reaction takes place? To investigate this,we were mindful of the fact that a reaction of this kind takesplace in a special environment where there is very little solvent(water) and the reaction is, each time, a “one off” event, so thatthermodynamically, it is not meaningful to think in terms offree energies. We resort instead to a consideration of reactionenthalpies as determined by ab initio quantum methods of theB3LYP/6-31G* type. Ribosomal peptide synthesis consistsessentially of a nucleophilic attack by the amino group of the(i+1)th residue at the carboxy terminal of the ith residue.Catalysis takes the form of specific acid or base catalytic groupslocated on RNA molecules in the ribosome peptidyltransferasesite. The reaction results in the net expulsion of a water mole-cule. The paradigm we are using for this reaction is the classicSN2 bimolecular reaction scheme (Ingold 1953). This reactionscheme prescribes a tetrahedral intermediate (sp3) in betweenthe starting and finishing structures which are of trigonal (sp2)geometry. We do not know enough about the charge status onthe atoms in this intermediate, nor which groups in the ribo-some they are in contact with, but some attempts were made tomodel this state. We focus rather on the ground state of whatwould be the product of the transpeptidation reaction, a closed-shell system where we can be reasonably certain about thegeometry and charge status. The only variables in our systemare the main chain torsion angles at the central carbon atom, asdescribed below.

Methods

Our starting structures are based on what we refer to asprimitive dipeptides: a central amino acid (the ith residue)with an acetyl group at its N-terminus representing electron-ically, if not biologically, the (i−1)th residue and a C-terminalmethylamide functional group as a surrogate for the (i+1)thresidue (see Fig. 1a). In this study, primitive dipeptides GD,AD, LD and ID as defined here, and with a backbone structureidentical to those used in previous work (Gould et al 1994;Wuet al 2010) were studied. These four primitive dipeptide struc-tures were selected in order to see what difference there wouldbe between an optically symmetric residue type (glycine) andasymmetric ones (alanine, leucine, isoleucine) and whetherthere would be any major difference between what is consid-ered to be an α-helix preferring residue type (leucine) oranother (isoleucine) which is stated (Bellesia et al 2010;Hovmoller et al 2002) to prefer an extended conformation(β-strand). We were further interested in investigating whatthe differences are between leucine and isoleucine, given thatthey are position isomers of one another, differing only in the

relative position of a single methyl group. In all, ∼15,000conformations were calculated for each of these primitivedipeptides, corresponding to 3° steps in each of the twodihedral angles. Further ∼40 structures which were 1° stepsof the enthalpic minimum structure for AD, LD and ID werestudied.

Construction of the starting structures for each of the manythousands of calculations was done within the YASARAprotein modelling program package (Krieger et al. 2002).Different conformers were constructed for each set, wherebythe Ci−1−Ni−CAi−Ci angles (theφ angle, in protein structureparlance) were stepped through at intervals of 3° (120 steps)while for each φ rotamer the Ni−CAi−Ci−Ni+1 angle (ψ) wasstepped through 120 steps of 3°. These structures were gen-erated automatically using a YASARA macro written for thispurpose. Figure 1 illustrates the φ and ψ dihedral angles thatare varied in order to explore torsion angle space. Figure 2provides an example of how the individual φ,ψ values aredistributed in this dihedral angle space for amino acid residuesin a typical globular protein (here “typical” means “represen-tative of theα/β class of proteins,” so chosen so as to populateas many energetically allowed areas of the dihedral space aspossible). There is a distinct clustering around two regions inparticular, the φ=−60°, ψ=−45° region typical of α-helicesand the φ=−135°, ψ=135° region typical of β-strands and,further, the polyproline (or collagen) helix at φ=−60°,ψ=160° (see Table 1 and Bywater et al 2001).

For each of the structures generated as above, densityfunctional theory (DFT) calculations with B3LYP functionaland ANO-L-VDZP basis set were conducted using Molcas7.8 code (Aquilante et al. 2010). The polarisable continuummodel (PCM)was used to simulate solvation effects (Karlströmet al 2003; Pomelli and Tomasi 1997). The dielectric constantof the solvent in PCM model can be chosen different from

Fig. 1 Structure of L-alanine primitive dipeptide showing atom labelling.The bonds denoting the φ and ψ dihedral angles are marked withcoloured discs

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dielectric constant of pure water in order to model the proteinenvironment. We made several sets of calculations with dielec-tric constants 1, 2.5 and 80, but we decided to settle for adielectric constant of 2.5 to reflect the water-poor environmentof the peptidyltransferase site and the extremely slow tumblingrate of an object as large as a ribosome.

Results

The results of the DFT energy calculations are displayed inFig. 3 for the four primitive dipeptides GD, AD, ID and LD,respectively. This figure represents the φ,ψ torsion anglespace as a 2D Matlab chart (although this is an unwrappedversion of what in reality is a sphere). Here, The DFTenergiesare used as a guide as to which conformations will be favouredby the sp2 product of the peptidyltransferase reaction. Weconsider only the energy of the product, but we have paid

considerable attention to the question of whether the sp3tetrahedral intermediate plays any role in deciding the finalconformation. We have modelled this intermediate and foundthat the energies are not at all sensitive to changes in mainchain dihedral angles in the way that ground state structuresare (data for these intermediates are available from authorRPB).

Common to the energy landscapes of all four primitivedipeptides (see Fig. 3) is a zone that stretches along theφ=0° axis that is strongly disfavoured due to steric clashesat these narrow torsion angles. The energetically favouredregions are shown in two shades of blue. Within the dark blue(lowest energy) regions there are, in the cases of AD, LD andID, deep and very narrow depressions with low energy, cor-responding to favoured regions in the energy landscape, thatare not easily displayed graphically, but they are describedbelow.

GD: Unlike all other natural amino acid types, glycinelacks a side chain. It therefore lacks mirror symmetry and itis also considerably more flexible than all other types. Glycineis usually considered to be able to adopt almost any kind ofsecondary structure (Liljas et al 2009; Bellesia et al 2010;Hovmoller et al 2002; Bywater et al 2001). This is borne outby the energy landscape that we calculate for GD, which issymmetrical and relatively “flat,” apart from the forbiddenridge referred to above. There are favoured regions (bluecolour) around φ=−72°, ψ≤0°, consistent with the standardright-handedα-helix, but this region stretches all the way overto the −108°≤φ≤−36°, 108°≤ψ≤180° region characteristic ofthe polyproline helix and also to the φ∼−140°, ψ≤140° β-strand region.

AD: The lowest energy conformation for AD is φ=−72°,ψ=144°, corresponding to the polyproline (collagen) helix(Table 1). This is shown as a dark blue region within the topright apex of the light blue “triangle.”Also within this triangleis a dark blue triangle which stretches from what would be the310 helix region up and “leftwards” towards the β-strandregion (φ∼−140°,ψ∼140°). It would not be correct to dismissthe importance of theα-helix, however, since this is in fact thesecond most stable structure, some 0.55 eV (53.1 kJ/mol) lessstable than the polyproline helix. It does not show up as darkblue because the region is extremely narrow, a deep depres-sionwith steep sides whichmakes it hardly visible on the scalerequired to make Fig. 3. In order to represent this steepdepression, a more “focused” figure for α-helix has beenprepared, see Fig. 4a. The comparable focused figure forpolyproline is shown in Fig. 4b. Note that for these focusedfigures, a log scale has had to be used, reflecting the “steep-ness of the depression” referred to earlier. The energy of theα-helix exceeds the β-strand by some 0.05 eV (4.82 kJ/mol).These results show a clear ordering of secondary structurepreferences for ADwith the ranking polyproline ≫α-helix>β-strand∼310 helix. Note that the 2D dihedral angle map for AD

Fig. 2 Plot of residue torsion angles from a selected set of proteins in 2Dφ,ψ (Ramachandran) space. This set (PDB IDs: 1dkfa, 1dqd, 1ulka, 5tim)is representative of water-soluble globular proteins with a good coverageof torsion angle space. The paucity of residues in the polyproline region(−108°≤φ≤−36°, 108°≤ψ≤180°) reflects the fact that this conformationis rare in globular proteins (while being very common in many types offibrous protein)

Table 1 Standard φ,ψ angles for helical structures, polyproline andprimitiveβ-strand (note: not sheet, since we are considering single chainsonly) taken from Liljas et al. (2009)

Secondary structure α-helix 310 helix Polyproline β-strand

φ −60 −75 −60 −135

ψ −45 −5 160 135

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(and all other residue types except glycine) is of courseasymmetrical.

ID: As in the case of AD, the polyproline region φ=−72°,ψ=144° wins over the α-helix region φ=−72°, ψ=−45°, thistime by 0.36 eV (34.7 kJ/mol) with theβ-strand region (whichshows up very prominently in Fig. 3) at 0.04 eV (3.86 kJ/mol)less than the α-helix. This is not entirely unexpected, sinceisoleucine is shown from experimental data (Bellesia et al2010; Hovmoller et al 2002) to prefer β-strand over α-helix.This in turn suggests that the difference in secondary structurepropensities for isoleucine as shown in these calculations isnot so much due to the torsional constraints which are inoperation in a primitive dipeptide, but only really manifestsitself once this amino acid type starts to accommodate itself inoligo- or polypeptide chains. In any case, the observed pref-erence for β in isoleucine (Bellesia et al 2010; Hovmoller et al2002) is not upheld in membrane-spanning peptides (Bywateret al 2001). There seems to be a ridge separating α-helix andβ-strand, coming where the 310 helix conformation would beexpected to reside, so the ranking in the case of ID would bepolyproline>α-helix∼β-strand ≫310 helix.

LD: As in the case of AD and ID, the polyproline regionφ=−72°, ψ=144° is strongly favoured with α-helix regionφ=−72°, ψ=−45° trailing, this time by 0.89 eV (85.9 kJ/mol).

Fig. 3 Peripherally, in clockwiseorder, GD, AD, ID and LDrepresenting the glycine, alanine,isoleucine and leucine primitivedipeptides, respectively. Thescale bar in the middle refers toall four figures and the units are inelectron volt. For each panel inthe figure, the abscissa representsthe φ angle and the ordinate the ψfor each residue type. The rangefor all axes stretches in theconventional Ramachandranmanner from −180° to +180°,left-to-right for the abscissae andbottom-to-top for the ordinates

-74-73

-72-71

-70-47

-46-45

-44-43

-4-3-2-1012345

logDFT

energy

phi

psi

-4-3-2-1012345

-74-73

-72-71

-70 142 143

144 145

146-2-101234

logDFT

energy

phi

psi

-2-101234

a

b

Fig. 4 Close-up sectors of the energy landscape for AD showing the α-helix (Fig. 4a) and polyproline helix (Fig. 4b). Note that a log scale hasbeen used for relative energies on the z-axis, reflecting the steepness of theenergy profile in these regions

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There is no sign of the ridge around the 310 region as in ID.The α-helix region now shows up as an isolated, once againvery narrow, region. The β-strand region has been consider-ably eroded but the 310 helix is populated. The ranking for LDis polyproline>α-helix>310 helix>β-strand. Leucine be-haves very differently to its position isomer, isoleucine(Fig. 3), in that it is known to favour α-helix over β-strand.

The three plots in Fig. 3 corresponding to AD, ID and LDneed some explanation. For each of them (as well as for GD),over 14,400DFTcalculations for all the structures produced at3° intervals were conducted. It would therefore be incorrect tosuggest that the very sharp depressions atφ=−72°,ψ=−45° inparticular, but also φ=−72°, ψ=144° are artefacts in any way.They are indeed much sharper than have been reported inprevious studies (Gould et al 1994; Wu et al 2010). But withso many thousands of structures calculated, the statistics areextremely robust. Nevertheless, an extra check was made byrunning calculations on ∼40 structures withφ,ψ angle steps of1° around these two minima and essentially, they only servedto emphasise the steepness of the walls of the minima (data notincluded in figures, but available on request).

Discussion

There has been much debate as to what conformation thenascent peptide adopts as it is synthesised and threads itsway through the exit tunnel on the ribosome. For reasons ofstability, and space within the confines of the tunnel, the α-helix always seemed to have been the foremost contender(Lim and Spirin 1984; Lim and Spirin 1986), and this notionis supported by the data presented here. Our minimum for ADis at φ=−72°, ψ=−45° while Gould et al. (1994) hasφ=−60.7° ψ=−40.7°. The latter value for φ is closer to theaverage values quoted in Table 1, while the converse is true forψ. A widely accepted range for these angles is φ=−64°±7°,ψ=−41°±7° (www.cryst.bbk.ac.uk). In any event, our φ=−72°, ψ=−45° value is identical for ID and LD as well as AD,which adds statistical weight to our findings. Other authorshave only studied GD and AD, but we have discovered manynew and important features of amino acid conformationalpropensities by including ID and LD. A further remarkconcerning earlier gas phase work is in order here, we aretrying to mimic the environment of a peptidyltransferase siteof a ribosome, which is what we are trying to accomplish. Thegas phase has different dielectric properties, and it has beenshown (Schäfer et al 1993) that CA–N distances areconsiderably shorter in proteins than in peptides in gas phase.

An extended chain or β-strand, as proposed in Wu et al.2010 is not prominent, based on these data (we cannot yetspeak of a β-sheet, as this is a post-translational development,after the strands have first been formed), except for GD and IDwhere it appears more accessible than for AD and LD.

We detect a deep, indeed, the deepest, depression for ID,LD and AD at φ=−72°, ψ=144°. This corresponds closely tothe polyproline conformation, which does not seem to havebeen remarked on before in this connection. A novel feature ofour work is that we show results for two other amino acidtypes, LD and ID. Like AD, they both have the deep minimaat theα-helix and polyproline loci, but otherwise they are verydifferent from one another. This illustrates an important pointthat has not been stressed before in the context of polypeptideconformation that just moving a methyl group from onecarbon atom to another can have profound consequences forprotein folding. Of course, the key to this pronounced changein properties is the fact that this apparently innocent transfer ofa methyl group results in the formation of a beta-branchedstructure (in isoleucine; and valine and threonine also havethis feature), which is known to introduce steric clashes thatdo not arise in the case of non-beta-branched residues.

We point out that the primitive dipeptides are indeed prim-itive from the point of view of secondary structure. This wasdefined above as “stretches of linearly repeated torsion anglesalong the chain,” and a dipeptide is hardly a repetition. For the“α-helix conformation,” we are not really observing an α-helix, since the minimum length of chain to form such a helixrequires four monomeric units (three for the 310 helix). Such ahelical construct requires a hydrogen bond between the N–Hof the ith and O=C of the (i+4)th residues ((i+3)rd for the 310helix), and it is remarkable that the conformation we observeis so stable in the absence of this hydrogen bond. Rather, weare observing a conformation that, given a chance to becomeextended as the peptidyltransferase reaction proceeds, couldgenerate an α-helix as a default structure. While this incipientα-helix may well continue with that conformation as it isdriven down the exit tunnel, there are many reasons why, atsome point, that will cease to be the case. The helix getsinterrupted by a turn or length random coil, or other secondarystructure may take over.

For the energetically favoured polyproline helix, this is notstabilised internally by hydrogen bonding at all. Hydrogenbonding in this conformation only becomes important post-translationally as stretches of polyproline form bundles as incollagen. But collagen is a fibrous protein, and the polyprolinehelix is in fact very rare in globular proteins (see Fig. 2 whichshows how underpopulated that region is). Furthermore,“polyproline” suggests very proline-rich sequences, whichagain are rare in globular proteins. Proline is typicallyregarded as a “helix breaker,” although a more nuanced ver-sion of this would be to reiterate a previously publishedstatement (Bywater et al. 2001) that proline forces a kink,while glycine permits a kink. Indeed, glycine is very versatilewhen it comes to how it accommodates with different second-ary structures as we show here. For proline, it would not bemeaningful to make a 2D φ,ψ map, since the φ angle inproline is locked into position at an angle of −60° (see Table 1)

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by the cyclic structure of the Ci−1−Ni−CAi−Ci angle. Inconsideration of the above, it seems likely that the“polyproline” conformation that we find in our calculationsreflects the fact that, while we have focused on globularproteins, the protein world is populated by fibrous proteinsas well. These are, as is well known (Liljas et al 2009), rich in(hydroxy-)proline and exhibit the polyproline structure veryprominently. This structure must also be catered for by thesame ribosomes that otherwise might be occupied withmanufacturing a globular protein. So, although our “α-helixconformation,” while being a strongly energetically favouredconformation, comes only second in rank to the polyprolineconformation, this observation masks the reality that after fourresidues, once the intra-chain hydrogen bonds begin to formand take effect, the “α-helix conformation” will emerge as themost favoured structure, becoming a real α-helix. Thepolyproline structure has no intra-chain hydrogen bondingpossibilities. For this reason, we conclude that our study sup-ports the α-helix model of incipient biosynthesis of polypep-tides on ribosomes, but does not constitute an absolute proof ofthis model. One would need to have more information aboutwhich functional groups inside the ribosome are in contactwith the primitive dipeptide and, ideally, crystal structure dataon peptides as they appear in the exit tunnel. Our data indicatethat the α-helix is at least one favoured default structure, butclearly, there are interruptions and other modifications thatmay take place along the folding pathway. The question wouldthen be, at what stage do these departures from the α-helicalgeometry take place, if and when they happen?

Conclusions

Many studies have previously been carried out in order todetermine the conformation of dipeptides. Usually, these havebeen conducted under gas phase conditions. This, however, isnot biologically interesting. Instead, we use dielectric condi-tions that reflect what the interior of a ribosome would be like.Most previous work has been conducted on dipeptides basedon glycine or alanine. We have done this too, but we haveincluded the corresponding structures based on leucine andisoleucine. In this way, a greater conformational repertoire isrevealed. Leucine is regarded as favouring the α-helix con-formation, while isoleucine is said to prefer the β-strand. Ourresults are in support of this, while for both of these residuetypes, as also for glycine and alanine, there is another favouredconformation, corresponding to the polyproline helix. We areacutely aware of the fact that our study has not been exhaus-tive. We have studied only four of the canonical set of 20residue types. While we have probed the question of α versusβ propensities for leucine and isoleucine, there are two other

beta-branched residue types, valine and threonine, that areworth investigating in this regard. Other comparative studiesof this kind, such as the difference between aspartic acid andasparaginewhich have been shown to populate the upper-rightquadrant of the Ramachandran plot, are certainly worth study-ing, and plans are in hand to extend this work to other residuetypes.

Acknowledgements The authors wish to record their indebtedness tothe late Björn Roos for inspiring leadership within and many creativecontributions to the field of quantum chemistry over so many years. Inparticular, theMolcas program, used in this work, is the outcome of manyyears of intensive research by him and his colleagues. We also thankElmar Krieger and Gert Vriend for making the YASARA modellingprogram available. This work was initiated by RPB during the tenure ofa Visiting Fellowship at Magdalen College, Oxford and this authorwishes to express his gratitude to the College for the excellent facilitiesand ambience under which that work was conducted. The reviewers are tobe thanked for many constructive suggestions; in particular, some pas-sages in the “Discussion” and “Conclusions” owe their origin to encour-aging remarks by one of the reviewers.

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