Ribbon structure stabilized by C10 and C12 turns in αγ hybrid peptide

The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc‐Gpn‐L‐Pro‐NHMe ( 1 ), Boc‐Aib‐Gpn‐L‐Pro‐NHMe ( 2 ), and Boc‐L‐Pro‐Aib‐Gpn‐L‐Pro‐NHMe ( 3 ). Peptides 1 and 2 adopt expanded 12‐membered (C₁₂) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II β‐turn (C₁₀) followed by the expanded C₁₂ helical γα turn. Both right‐handed and left‐handed helical conformations for Aib residue are observed in peptides 2 and 3 , respectively Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Terminal effect of chiral residue on helical screw sense in achiral peptides

To understand the terminal effect of chiral residue for determining a helical screw sense, we adopted five kinds of peptides I – V containing N‐ and/or C‐terminal chiral Leu residue(s): Boc–L ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( I ), Boc–(Aib–ΔPhe)₂–L ‐Leu–OMe ( II ), Boc–L ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( III ), Boc–D ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( IV ), and Boc–D ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( V ). The segment –(Aib–ΔPhe)₂– was used for a backbone composed of two “enantiomeric” (left‐/right‐handed) helices. Actually, this could be confirmed by ¹H‐nmr [nuclear Overhauser effect (NOE) and solvent accessibility of NH resonances] and CD spectroscopy on Boc–(Aib–ΔPhe)₂–Aib–OMe, which took a left‐/right‐handed 3₁₀‐helix. Peptides I – V were also found to take 3₁₀‐type helical conformations in CDCl₃, from difference NOE measurement and solvent accessibility of NH resonances. Chloroform, acetonitrile, methanol, and tetrahydrofuran were used for CD measurement. The CD spectra of peptides I – III in all solvents showed marked exciton couplets with a positive peak at longer wavelengths, indicating that their main chains prefer a left‐handed screw sense over a right‐handed one. Peptide V in all solvents showed exciton couplets with a negative peak at longer wavelengths, indicating it prefers a right‐handed screw sense. Peptide IV in chloroform showed a nonsplit type CD pattern having only a small negative signal around 280 nm, meaning that left‐ and right‐handed helices should exist with almost the same content. In the other solvents, peptide IV showed exciton couplets with a negative peak at longer wavelengths, corresponding to a right‐handed screw sense. From conformational energy calculation and the above ¹H‐nmr studies, an N‐ or C‐terminal L ‐Leu residue in the lowest energy left‐handed 3₁₀‐helical conformation was found to take an irregular conformation that deviates from a left‐handed helix. The positional effect of the L ‐residue on helical screw sense was discussed based on CD data of peptides I – V and of Boc–(L ‐Leu–ΔPhe)_n–L ‐Leu–OMe (n = 2 and 3). © 1999 John Wiley & Sons, Inc. Biopoly 49: 551–564, 1999     

A comparison of the different helices adopted by ��- and ��-peptides suggests different reasons for their stability

The right‐handed α‐helix is the dominant helical fold of α‐peptides, whereas the left‐handed 3₁₄‐helix is the dominant helical fold of β‐peptides. Using molecular dynamics simulations, the properties of α‐helical α‐peptides and 3₁₄‐helical β‐peptides with different C‐terminal protonation states and in the solvents water and methanol are compared. The observed energetic and entropic differences can be traced to differences in the polarity of the solvent‐accessible surface area and, in particular, the solute dipole moments, suggesting different reasons for their stability.     

Angiotensin II restricted analogs with biological activity in the erythrocytic cycle of Plasmodium falciparum

The anti‐plasmodial activity of conformationally restricted analogs of angiotensin II against Plasmodium gallinaceum has been described. To observe activity against another Plasmodium species, invasion of red blood cells by Plasmodium falciparum was analyzed. Analogs restricted with lactam or disulfide bridges were synthesized to determine their effects and constraints in the peptide–parasite interaction. The analogs were synthesized using tert‐butoxycarbonyl and fluoromethoxycarbonyl solid phase methods, purified by liquid chromatography, and characterized by mass spectrometry. Results indicated that the lactam bridge restricted analogs 1 (Glu‐Asp‐Arg‐Orn ‐Val‐Tyr‐Ile‐His‐Pro‐Phe) and 3 (Asp‐Glu‐Arg‐Val‐Orn ‐Tyr‐Ile‐His‐Pro‐Phe) showed activity toward inhibition of ring formation stage of P. falciparum erythrocytic cycle, preventing invasion in about 40% of the erythrocytes. The disulfide‐bridged analog 10 (Cys‐Asp‐Arg‐Cys ‐Val‐Tyr‐Ile‐His‐Pro‐Phe) was less effective yet significant, showing a 25% decrease in infection of new erythrocytes. In all cases, the peptides presented no pressor activity, and hydrophobic interactions between the aromatic and alkyl amino acid side chains were preserved, a factor proven important in efficacy against P. gallinaceum. In contrast, hydrophilic interactions between the Asp¹ carboxyl and Arg² guanidyl groups proved not to be as important as they were in the case of P. gallinaceum, while interactions between the Arg² guanidyl and Tyr⁴ hydroxyl groups were not important in either case. The β‐turn conformation was predominant in all of the active peptides, proving importance in anti‐plasmodial activity. This approach provides insight for understanding the importance of each amino acid residue on the native angiotensin II structure and a new direction for the design of potential chemotherapeutic agents. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

A Helical Polyphenylacetylene Having Amino Alcohol Moieties Without Chiral Side Groups as a Chiral Ligand for the Asymmetric Addition of Diethylzinc to Benzaldehyde

One‐handed helical polyphenylacetylenes having achiral amino alcohol moieties, but no chiral side groups, were synthesized by the helix‐sense‐selective copolymerization of an achiral phenylacetylene having an amino alcohol side group with a phenylacetylene having two hydroxyl groups. Since the resulting helical copolymers were successfully utilized as chiral ligands for the enantioselective alkylation of benzaldehyde with diethylzinc, we can conclude that the main‐chain chirality based on the one‐handed helical conformation is useful for the chiral catalysis of an asymmetric reaction for the first time. The enantioselectivities of the reaction were controlled by the optical purities of the helical polymer ligands. In addition, the polymer ligands could be easily recovered by precipitation after the reaction. Chirality 27:454–458, 2015. © 2015 Wiley Periodicals, Inc.     

Studying the Structural and Folding Features of Long‐Sequence Trichobrachin Peptides

In this theoretical study, the folding processes of long‐sequence trichobrachin peptides (i.e., TB IIb peptides) were investigated by molecular dynamics methods. The formation of various helical structures (i.e., 3₁₀‐, α‐, and left‐handed α‐helices) was studied with regard to the entire sequence of peptides, as well as to each amino acid. The results pointed out that TB IIb molecules showed a propensity to form helical conformations, and they could be characterized by 3₁₀‐helical structure rather than by α‐helical structure. The formation of local (i.e., i←i+3 and i←i+4) as well as of non‐local (i.e., i←i+n, where n>4; and all i→i+n) H‐bonds was also examined. The results revealed that the occurrence of local, helix‐stabilizing H‐bonds was in agreement with the appearance of helical conformations, and the non‐local H‐bonds did not produce relevant effects on the evolution of helical structures. Based on the data obtained by our structural investigation, differences were observed between the TB IIb peptides, according to the type of amino acid located in the 17th position of their sequences. In summary, the folding processes were explored for TB IIb molecules, and our theoretical study led to the conclusion that these long‐sequence peptaibols showed characteristic structural and folding features.     

Conformational preferences of a short Aib/Ala‐based water‐soluble peptide as a function of temperature

The amino acid Aib predisposes a peptide to be helical with context‐dependent preference for either 3₁₀‐ or α‐ or a mixed helical conformation. Short peptides also show an inherent tendency to be unfolded. To characterize helical and unfolded states adopted by water‐soluble Aib‐containing peptides, the conformational preference of Ac‐Ala‐Aib‐Ala‐Lys‐Ala‐Aib‐Lys‐Ala‐Lys‐Ala‐Aib‐Tyr‐NH₂ was determined by CD, NMR and MD simulations as a function of temperature. Temperature‐dependent CD data indicated the contribution of two major components, each an admixture of helical and extended/polyproline II structures. Both right‐ and left‐handed helical conformations were detected from deconvolution of CD data and ¹³C NMR experiments. The presence of a helical backbone, more pronounced at the N‐terminal, and a temperature‐induced shift in α‐helix/3₁₀‐helix equilibrium, more pronounced at the C‐terminal, emerged from NMR data. Starting from polyproline II, the N‐terminal of the peptide folded into a helical backbone in MD simulations within 5 ns at 60°C. Longer simulations showed a mixed‐helical backbone to be stable over the entire peptide at 5°C while at 60°C the mixed‐helix was either stable at the N‐terminus or occurred in short stretches through out the peptide, along with a significant population of polyproline II. Our results point towards conformational heterogeneity of water‐soluble Aib‐based peptide helices and the associated subtleties. The problem of analyzing CD and NMR data of both left‐ and right‐handed helices are discussed, especially the validity of the ellipticity ratio [θ]₂₂₂/[θ]₂₀₇, as a reporter of α‐/3₁₀‐ population ratio, in right‐ and left‐handed helical mixtures. Proteins 2009. © 2008 Wiley‐Liss, Inc.     

Crystal structure of the collagen model peptide (Pro‐Pro‐Gly)4‐Hyp‐Asp‐Gly‐(Pro‐Pro‐Gly)4 at 1.0 Å resolution

The single‐crystal structure of the collagen‐like peptide (Pro‐Pro‐Gly)₄‐Hyp‐Asp‐Gly‐(Pro‐Pro‐Gly)₄, was analyzed at 1.02 Å resolution. The overall average helical twist (θ = 49.6°) suggests that this peptide adopts a 7/2 triple‐helical structure and that its conformation is very similar to that of (Gly‐Pro‐Hyp)₉, which has the typical repeating sequence in collagen. High‐resolution studies on other collagen‐like peptides have shown that imino acid‐rich sequences preferentially adopt a 7/2 triple‐helical structure (θ = 51.4°), whereas imino acid‐lean sequences adopt relaxed conformations (θ < 51.4°). The guest Gly‐Hyp‐Asp sequence in the present peptide, however, has a large helical twist (θ = 61.1°), whereas that of the host Pro‐Pro‐Gly sequence is small (θ = 46.7°), indicating that the relationship between the helical conformation and the amino acid sequence of such peptides is complex. In the present structure, a strong intermolecular hydrogen bond between two Asp residues on the A and B strands might induce the large helical twist of the guest sequence; this is compensated by a reduced helical twist in the host, so that an overall 7/2‐helical symmetry is maintained. The Asp residue in the C strand might interact electrostatically with the N‐terminus of an adjacent molecule, causing axial displacement, reminiscent of the D‐staggered structure in fibrous collagens. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 436–447, 2013.     

Structure of the hypothetical protein Ton 1535 from Thermococcus onnurineus NA1 reveals unique structural properties by a left‐handed helical turn in normal α‐solenoid protein

The crystal structure of Ton1535, a hypothetical protein from Thermococcus onnurineus NA1, was determined at 2.3 Å resolution. With two antiparallel α‐helices in a helix‐turn‐helix motif as a repeating unit, Ton1535 consists of right‐handed coiled N‐ and C‐terminal regions that are stacked together using helix bundles containing a left‐handed helical turn. One left‐handed helical turn in the right‐handed coiled structure produces two unique structural properties. One is the presence of separated concave grooves rather than one continuous concave groove, and the other is the contribution of α‐helices on the convex surfaces of the N‐terminal region to the extended surface of the concave groove of the C‐terminal region and vice versa. Proteins 2014; 82:1072–1078. © 2013 Wiley Periodicals, Inc.     

REVERSAL OF HELIX ORIENTATION IN THE CYANOBACTERIUM ARTHROSPIRA1

A survey of the morphological characters of 36 clonal axenic strains of Arthrospira showed that 34 had helical and 2 had straight trichomes. Of those with helical trichomes, five were right‐handed and 29 left‐handed. After repeated subculture for 1 year, the orientation of one helical strain (D893) had changed from right‐ to left‐handed, suggesting a probable genetic shift. The influence of environmental factors on helix orientation was tested on a subset of 10 strains. A temperature upshift from 30 to 32–34° C for 7 days led to a change in orientation in three strains (D918/H, D923, D925). Incubation at 32° C (D918/H, D923) or 34° C (D925) for periods less than needed for the morphological change to show still permitted the change to take place subsequently, when the temperature was reduced to 30° C; however, further subculture at 30° C led to the orientation reverting to its original state. In strain D925, but not the other nine strains, continuous shaking at 30° C also led to a change in helix orientation. In this case, some trichomes showed both orientations in a single trichome, with a snag at the point of reversion. A repeat survey of the stock cultures of all 34 strains after 2 years showed that another strain (D918/H) had now changed orientation from right‐handed to left‐handed. These observations are compared with the behavior of other helical structures in the literature, including filamentous Bacillus subtilis mutants and helix reversal in tendrils of climbing plants.     

Conformations of peptides containing a chiral cyclic α, α‐disubstituted α‐amino acid within the sequence of Aib residues

A single chiral cyclic α,α‐disubstituted amino acid, (3S,4S)‐1‐amino‐(3,4‐dimethoxy)cyclopentanecarboxylic acid [(S,S)‐Ac₅c^dOM], was placed at the N‐terminal or C‐terminal positions of achiral α‐aminoisobutyric acid (Aib) peptide segments. The IR and ¹H NMR spectra indicated that the dominant conformations of two peptides Cbz‐[(S,S)‐Ac₅c^dOM]‐(Aib)₄‐OEt ( 1) and Cbz‐(Aib)₄‐[(S,S)‐Ac₅c^dOM]‐OMe (2) in solution were helical structures. X‐ray crystallographic analysis of 1 and 2 revealed that a left‐handed (M) 3₁₀‐helical structure was present in 1 and that a right‐handed (P) 3₁₀‐helical structure was present in 2 in their crystalline states. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

The effect of a terminal chiral residue on the helicity of a peptide chain

Summary We studied the effect of incorporating a chiral terminal amino acid residue (L-leucine) on the helical screw sense of a previously characterized achiral helical polypeptide module-[glycine-(C^α,α-di-n-butylglycine)-glycine]₂-by means of CD spectroscopy and conclude that the presence of this residue at the carboxyl terminal induces a predominantly left handed helical conformation of the helix.     

Designing of peptides with left handed helical structure by incorporating the unusual amino acids

The conformational behaviour of delta Ala has been investigated by quantum mechanical method PCILO in the model dipeptide Ac-delta Ala-NHMe and in the model tripeptides Ac-X-delta Ala-NHMe with X = Gly, Ala, Val, Leu, Abu and Phe and is found to be quite different. The computational results suggest that in the model tripeptides the most stable conformation corresponds to phi 1 = -30 degrees, psi 1 = 120 degrees and phi 2 = psi 2 = 30 degrees in which the > C = 0 of the acetyl group is involved in hydrogen bond formation with N-H of the amide group. Similar results were obtained for the conformational behaviour of D-Ala in Ac-D-Ala-NHMe and Ac-Ala-D-Ala-NHMe. The conformational behaviour of the amino acids delta Ala, D-Ala, Val and Aib in model tripeptides have been utilized in the designing of left handed helical peptides. It is shown that the peptide HCO-(Ala-D-Ala)3-NHMe can adopt both left and right handed helix whereas in the peptide Ac-(Ala-delta Ala)3-NHMe the lowest energy conformer is beta-bend ribbon structure. Left handed helical structure with phi = 30 degrees, psi = 60 degrees for D-Ala residues and phi = psi = 30 degrees for delta Ala is found to be more stable by 4 kcal mole-1 than the corresponding right handed helical structure for the peptide Ac-(D-Ala-delta Ala)3-NHMe. In both the peptides Ac-(Val-delta Ala)3-NHMe and Ac-(D-Val-delta Ala)3-NHMe the most stable conformer is the left handed helix. Comparisons of results for Ac-(Ala-delta Ala)3-NHMe and Ac(Val-delta Ala)3-NHMe and Ac-(D-Ala-delta Ala)3-NHMe and Ac-(D-Val-delta Ala)3-NHMe also reveal that the Val residues facilitate the population of 3(10) left handed helix over the other conformers. It is also shown that the conformational behaviour of Aib residue depends on the chirality of neighbouring amino acids, i.e. Ac-(Aib-Ala)3-NHMe adopts right handed helical structure whereas Ac-(Aib-D-Ala)3-NHMe is found to be in left handed helical structure.     

The primary structure of the β-subunit of protocatechuate 3,4-dioxygenase from Pseudomonas aeruginosa

The complete amino acid sequence of the β-subunit of protocatechuate 3,4-dioxygenase was determined. The β-subunit contained four methionine residues. Thus, five peptides were obtained after cleavage of the carboxymethylated β-subunit with cyanogen bromide, and were isolated on Sephadex G-75 column chromatography. The amino acid sequences of the cyanogen bromide peptides were established by characterization of the peptides obtained after digestion with trypsin, chymotrypsin, thermolysin, or Staphylococcus aureus protease. The major sequencing techniques used were automated and manual Edman degradations. The five cyanogen bromide peptides were aligned by means of the amino acid sequences of the peptides containing methionine purified from the tryptic hydrolysate of the carboxymethylated β-subunit. The amino acid sequence of all the 238 residues was as follows: ProAlaGlnAspAsnSerArgPheValIleArgAsp ArgAsnTrpHis ProLysAlaLeuThrPro-Asp — TyrLysThrSerIleAlaArg SerProArgGlnAla LeuValSerIleProGlnSer — IleSerGluThrThrGly ProAsnPheSerHisLeu GlyPheGlyAlaHisAsp-His — AspLeuLeuLeuAsnPheAsn AsnGlyGlyLeu ProIleGlyGluArgIle-Ile — ValAlaGlyArgValValAsp GlnTyrGlyLysPro ValProAsnThrLeuValGluMet — TrpGlnAlaAsnAla GlyGlyArgTyrArg HisLysAsnAspArgTyrLeuAlaPro — LeuAspProAsn PheGlyGlyValGly ArgCysLeuThrAspSerAspGlyTyrTyr — SerPheArg ThrIleLysProGlyPro TyrProTrpArgAsnGlyProAsnAsp — TrpArgProAla HisIleHisPheGlyIle SerGlyProSerIleAlaThr-Lys — LeuIleThrGlnLeuTyr PheGluGlyAspPro LeuIleProMetCysProIleVal — LysSerIleAlaAsn ProGluAlaValGlnGln LeuIleAlaLysLeuAspMetAsnAsn — AlaAsnProMet AsnCysLeuAlaTyr ArgPheAspIleValLeuArgGlyGlnArgLysThrHis PheGluAsnCys. The sequence published earlier in summary form (Iwaki et al., 1979, J. Biochem.86, 1159–1162) contained a few errors which are pointed out in this paper.     

Stereochemistry of Schellman motifs in peptides: Crystal structure of a hexapeptide with a C‐terminus 6 → 1 hydrogen bond

The Schellman motif is a widely observed helix terminating structural motif in proteins, which is generated when the C‐terminus residue adopts a left‐handed helical (α_L) conformation. The resulting hydrogen‐bonding pattern involves the formation of an intramolecular 6 → 1 interaction. This helix terminating motif is readily mimicked in synthetic helical peptides by placing an achiral residue at the penultimate position of the sequence. Thus far, the Schellman motif has been characterized crystallographically only in peptide helices of length 7 residues or greater. The structure of the hexapeptide Boc–Pro–Aib–Gly–Leu–Aib–Leu–OMe in crystals reveal a short helical stretch terminated by a Schellman motif, with the formation of 6 → 1 C‐terminus hydrogen bond. The crystals are in the space group P2₁2₁2₁ with a = 18.155(3) Å, b = 18.864(8) Å, c = 11.834(4) Å, and Z = 4 . The final R₁ and wR₂ values are 7.68 and 14.6%, respectively , for 1524 observed reflections [F_o ≥ 3ς(F_o)]. A 6 → 1 hydrogen bond between Pro(1)CO · · · Leu(6)NH and a 5 → 2 hydrogen bond between Aib(2)CO · · · Aib(5)NH are observed. An analysis of the available oligopeptides having an achiral Aib residue at the penultimate position suggests that chain length and sequence effects may be the other determining factors in formation of Schellman motifs. © 1999 John Wiley & Sons, Inc. Biopoly 50: 13–22, 1999     

Right‐ and left‐handed three‐helix proteins. II. Similarity and differences in mechanical unfolding of proteins

Here, we study mechanical properties of eight 3‐helix proteins (four right‐handed and four left‐handed ones), which are similar in size under stretching at a constant speed and at a constant force on the atomic level using molecular dynamics simulations. The analysis of 256 trajectories from molecular dynamics simulations with explicit water showed that the right‐handed three‐helix domains are more mechanically resistant than the left‐handed domains. Such results are observed at different extension velocities studied (192 trajectories obtained at the following conditions: v = 0.1, 0.05, and 0.01 Å ps^?1, T = 300 K) and under constant stretching force (64 trajectories, F = 800 pN, T = 300 K). We can explain this by the fact, at least in part, that the right‐handed domains have a larger number of contacts per residue and the radius of cross section than the left‐handed domains. Proteins 2014; 82:90–102. © 2013 Wiley Periodicals, Inc.     

Self‐assembling study of sarcolipin and its mutants in multiple molecular dynamic simulations

The Sarcolipin (SLN) is a single trans‐membrane protein that can self‐assembly to dimer and oligomer for playing importantphysiological function. In this work, we addressed the dimerization of wild type SLN (wSLN) and its mutants (mSLNs) – I17A and I20A, using both coarse‐grained (CG) and atomistic (AT) molecular dynamics (MD) simulations. Our results demonstrated that wSLN homodimer assembled as a left‐handed helical complex, while mSLNs heterodimers assembled as right‐handed complexes. Analysis of residue‐residue contacts map indicated that isoleucine (Ile)‐leucione (Leu) zipper domain played an important role in dimerization. The potential of mean force (PMF) demonstrated that wSLN homodimer was more stable than mSLNs heterodimers. Meanwhile, the mSLNs heterodimers preferred right‐handed rather than left‐handed helix. AT‐MD simulations for wSLN and mSLNs were also in line with CG‐MD simulations. These results provided the insights for understanding the mechanisms of SLNs self‐assembling. Proteins 2017; 85:1065–1077. © 2017 Wiley Periodicals, Inc.     

Synthesis of a Fluorine‐Containing Cis‐Cisoidal One‐Handed Helical Polyphenylacetylene and Application of Highly Selective Photocyclic Aromatization Product on Oxygen Permselective Membrane

A novel phenylacetylene monomer having a perfluorinated alkyl group ( M-F ) was synthesized and polymerized in a chiral catalytic system to yield a one‐handed helical polymer. The ability and efficiency of the chiral induction of the fluorine‐containing monomer in the helix‐sense‐selective polymerization (HSSP) was much higher than those of a monomer having the corresponding alkyl group ( M-H ) we reported before. The resulting polymer P-F showed cis‐cisoidal one‐handed helical conformation, and was suitable for highly selective photocyclic aromatization (SCAT) to give a 2D surface modifier ( T-F ). Oxygen permselectivity through a base polymer membrane was highly enhanced from 1.83 to 2.36 by adding a small amount (1–5 wt%) of the 2D surface modifier T-F . The improvement was thought to be caused by improvement of solution selectivity on the membrane surface which the 2D surface modifier effectively covered. Chirality 27:459–463, 2015. © 2015 Wiley Periodicals, Inc.     

Structures of peptides from α-amino acids methylated at the α-carbon,

The structural preferences of peptides (and depsipeptides) from the achiral MeAib and Hib residues, and the chiral Iva, (αMe) Val, (αMe) Leu, and (αMe) Phe residues, as determined by conformational energy computations, x-ray diffraction analyses, and ¹H-nmr and spectroscopic studies, are reviewed and compared with literature data on Aib-containing peptides. The results obtained indicate that helical structures are preferentially adopted by peptides rich in these α-amino acids methylated at the α-carbon. Intriguing experimental findings on the impact of the chirality of Iva, (αMe) Val, and (αMe) Phe residues on helix screw sense are illustrated. © 1993 John Wiley & Sons, Inc.     

Alpha helical crossovers favor right‐handed supersecondary structures by kinetic trapping: The phone cord effect in protein folding

The remarkable predominance of right‐handedness in beta‐alpha‐beta helical crossovers has been previously explained in terms of thermodynamic stability and kinetic accessibility, but a different kinetic trapping mechanism may also play a role. If the beta‐sheet contacts are made before the crossover helix is fully formed, and if the backbone angles of the folding helix follows the energetic pathway of least resistance, then the helix would impart a torque on the ends of the two strands. Such a torque would tear apart a left‐handed conformation but hold together a right‐handed one. Right‐handed helical crossovers predominate even in all‐alpha proteins, where previous explanations based on the preferred twist of the beta sheet do not apply. Using simple molecular simulations, we can reproduce the right‐handed preference in beta‐alpha‐beta units, without imposing specific beta‐strand geometry. The new kinetic trapping mechanism is dubbed the “phone cord effect” because it is reminiscent of the way a helical phone cord forms superhelices to relieve torsional stress. Kinetic trapping explains the presence of a right‐handed superhelical preference in alpha helical crossovers and provides a possible folding mechanism for knotted proteins.