Intrinsically Stable Secondary Structure Elements of Proteins: A Comprehensive Study of Folding Units of Proteins by Computation and by Analysis of Data Determined by X‐ray Crystallography

Abstract

Different protein architectures show strong similarities regardless of their amino acid composition: the backbone folds of the different secondary structural elements exhibit nearly identical geometries. To investigate the principles of folding and stability properties, oligopeptide models (that is, HCO-(NH-L-CHR-CO)(n)-NH(2)) have been studied. Previously, ab initio structure determinations have provided a small amount of information on the conformational building units of di- and tripeptides. A maximum of nine differently folded backbone types is available for any natural alpha-amino acid residue, with the exception of proline. All of these conformers have different relative energies. The present study compiles an ab inito database of optimized HCO-(L-Xxx)(n)-NH(2) structures, where 1<or=n<or=8 and Xxx=Ala or Gly. All homoconformers (alpha helix, beta sheet, collagen helix, etc.) of the different backbone folds were optimized, along with additional beta-turn-type heteroconformers. The comprehensive analysis of more than 150 fully optimized polyalanine and polyglycine structures reveals the same energy-preference profile of major secondary structures as is found in globular proteins. The analysis of relative energies at three different levels of theory (RHF/3-21G, RHF/6-311++G(d,p)//RHF/3-21G, and RHF/6-311++G(d,p)) for the above-mentioned achiral (Xxx=Gly) and chiral (Xxx=Ala) molecular structures shows how these common secondary structure elements gradually become more and more stable folds in the oligopeptides as the length of the peptide chain increases. This indicates that stability (local energy preference) of conformational building units seems to be a major driving force in peptide and protein folding. Furthermore, the preferred conformers of the gas phase are rather similar to those observed in proteins crystallized from aqueous media. Indeed, the relative energies for the different computed conformers show remarkable agreement with the frequency of occurrence of the same structural motifs retrieved from a nonhomologous X-ray crystallography database.

Origin of intrinsic 310‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

“…As shown in Table 1 and Figure 1, the stabilization of the helical versus extended conformation strongly depends on the number of residues in the chain, and in agreement with previous results for polyalanine and polyglycine, 13,18,22 cooperatively increases as the chain length increases. Next, we examine how this stability depends on the identity of amino acids and whether it is driven only by hydrogen bonding.…”

“…1, Table 1). In agreement with others, 13,18,20,22 helices in the gas phase adopt a 3 10 -helix conformation (which we call ''helical'' for simplicity) rather than an -helix, which, for shorter peptides (up to *20 residues), 18 is higher in energy and is not stable for lengths shorter than eight residues. 18 This is due to the formation of an additional hydrogen bond in a 3 10 -helix compared with a canonical -helix at the cost of breaking the parallel alignment of the hydrogen bonds.…”

“…Rather, in agreement with previous work, they are higher in energy than extended conformations. 15,22 However, when the polypeptide chain becomes longer, the helical conformation becomes more and more stable for all four types of amino acids ( Fig. 1, Table 1).…”

“…The influence of single amino acid replacements in glycine pentapeptides 21 on helix stability were also studied, using mixed QM/semiempirical calculations (DFT/AM1). The relative stabilities of the most common secondary structure motifs of pAla and polyglycine (up to 8 residues) were studied by Perczel et al 22 for fully optimized peptide geometries. At a medium level of QM (HF/6-311þþg**) accuracy, they showed that the studied secondary structure motifs are intrinsically stable in the gas phase, and that the helical conformation (which in the gas phase is closer to a 3 10 -helix than to an -helix) is the most stable conformation for peptides longer than three-residues with its relative stability versus the extended conformation increasing with peptide length.…”

Efficient model chemistries for peptides. I. General framework and a study of the heterolevel approximation in RHF and MP2 with Pople split‐valence basis sets

“…In any bottom-up approach to the still unsolved protein folding problem [1][2][3][4], the characterization of the conformational behaviour of short peptides [5][6][7][8][9][10][11][12] constitutes an unavoidable first step. If high accuracy of the treatment is sought, numerically expensive methods must be used to calculate the physical properties of these protein subunits.…”