Structural studies of C-amidated amino acids and peptides: crystal structures of Z-Gly-Phe-NH2, Tyr-Lys-NH2, and Asp-Phe-NH2

As part of the series investigating the structural features of C-terminal amidated amino acids and peptides, three crystal structures of Z-Gly-Phe-NH2, Tyr-Lys-NH2, and Asp-Phe-NH2 were analyzed by the X-ray diffraction method, and their molecular conformations and intermolecular interactions were investigated. Although the respective dipeptides exhibited an energetically allowable torsion angle concerning each backbone or side chain, the observed extended (Z-Gly-Phe-NH2, Asp-Phe-NH2) and folded (Tyr-Lys-NH2) conformations were considerably different from those of the corresponding unamidated peptides, due to the conformational flexibility of the respective dipeptides. The comparison between the crystal packings of the amidated and unamidated dipeptides indicated that the C-terminal amides tend to associate with the same neighboring group through hydrogen bonds, in which both the amide NH and O=C groups participate, while the unamidated peptides prefer a linear molecular connection, where both or either of the two carboxyl oxygens participate in the hydrogen bond formation. The difference in hydrogen bonding ability between the C-terminal amide and carboxyl groups has been considered to be based on the structural data of the related peptides analyzed so far.     

Computational Exploration of Conformations of Glycine-Arginine and a Deduced Model on Global Minimum Configurations of Dipeptides in Gas Phase

An extensive computational study on the conformations of gaseous dipeptide glycinearginine, GlyArg, has been performed. A large number of trail structures were generated by systematically sampling the potential energy surface (PES) of GlyArg. The trial structures were successively optimized with the methods of PM3, HF/3-21G^*, BHandHLYP/6-31G^*, and BHandHLYP/6-311++G^** in order to reliably find the low energy conformations. The conformational energies were finally determined with the methods of BHandHLYP, camB3LYP, B97D, and MP2 using the basis set of 6-311++G(3df,3pd). The results establish firmly that gaseous GlyArg exists primarily in its canonical form, in sharp contrast with ArgGly that adopts the zwitterionic form. Important data such as the rotational constants, dipole moments, vertical ionization energies, temperature distributions and IR spectra of the low energy conformers are represented for the understanding of the future experiments. Moreover, considering the global minima of all amino acids and many dipeptides, combined with the hydrophobicities of amino acids, a model predicting whether the global minimum configuration of a dipeptide is canonical or zwitterionic is developed.     

Delta-peptides and delta-amino acids as tools for peptide structure design--a theoretical study

An overview on all possible helix types in oligomers of delta-amino acids (delta-peptides) and their stabilities is given on the basis of a systematic conformational analysis employing various methods of ab initio MO theory (HF/6-31G*, B3LYP/6-31G*, PCM//HF/6-31G*). A wide variety of novel helical structures with hydrogen-bonded pseudocycles of different size are predicted. Since a delta-amino acid constituent may replace a dipeptide unit in alpha-peptides, there are close relationships between the secondary structures of peptides with delta-amino acid residues and typical secondary structures of alpha-peptides. However, the preference of gauche conformations at the central C(beta)-C(gamma) bonds of delta-amino acids, which correspond to the peptide linkages in alpha-peptides, over staggered ones makes completely novel structure alternatives for helices and turns more probable. The peculiarities of beta-turn formation by sugar amino acids derived from delta-amino acids are compared with the turn formation in delta-amino acid residues and in alpha-peptides. The considerable potential of secondary structure formation in delta-peptides and single delta-amino acid constituents predicted by ab initio MO theory may stimulate experimental work in the field of peptide and foldamer design.     

Helically chiral ferrocene peptides containing 1'-aminoferrocene-1-carboxylic acid subunits as turn inducers

We present a detailed structural study of peptide derivatives of 1'-aminoferrocene-1-carboxylic acid (ferrocene amino acid, Fca), one of the simplest organometallic amino acids. Fca was incorporated into di- to pentapeptides with D- and L-alanine residues attached to either the carboxy or amino group, or to both. Crystallographic and spectroscopic studies (circular dicroism (CD), IR, and NMR) of about two dozen compounds were used to gain a detailed insight into their structures in the solid state as well as in solution. Four derivatives were characterized by single-crystal X-ray analysis, namely Boc-Fca-Ala-OMe (16), Boc-Fca-D-Ala-OMe (17), Boc-Fca-beta-Ala-OMe (18), and Boc-Ala-Fca-Ala-Ala-OMe (21) (Boc=tert-butyloxycarbamyl). CD spectroscopy is an extremely useful tool to elucidate the helical chirality of the metallocene core. Unlike in all other known ferrocene peptides, the helical chirality of the ferrocene is governed solely by the chirality of the amino acid attached to the N terminus of Fca. Depending on the degree of substitution of both cyclopentadiene (Cp) rings, different hydrogen-bonding patterns are realized. (1)H NMR and IR spectroscopy, together with the results from X-ray crystallography, give detailed information regarding not only the hydrogen-bonding patterns of the compounds, but also the equilibria between different conformers in solution. Differences in chemical shifts of NH protons in dimethyl sulfoxide ([D(6)]DMSO) and CDCl(3), that is, the variation ratio (vr), is used for the first time as a measure of the hydrogen-bonding strength of individual COHN bonds in ferrocenoyl peptides. In dipeptides with one intramolecular hydrogen bond between the pendant chains, for example, in dipeptide 16, an equilibrium between hydrogen-bonded and open forms is observed, as testified by a vr value of around 0.5. Higher peptides, such as tetrapeptide 21, are able to form two intramolecular hydrogen bonds stabilizing one single conformation in CDCl(3) solution (vr approximately 0). Due to the low barrier of Cp-ring rotation, new and unnatural hydrogen-bonding patterns are emerging. The systematic work described herein lays a solid foundation for the rational design of metallocene peptides with unusual structures and properties.     

Conformational preferences of proline analogues with different ring size

The conformational study on L-azetidine-2-carboxylic acid (Ac-Aze-NHMe, the Aze dipeptide) and (S)-piperidine-2-carboxylic acid (Ac-Pip-NHMe, the Pip dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the differences in conformational preferences and cis-trans isomerization for proline residue and its analogues with different ring size in the gas phase and in solution (chloroform and water). The change of ring size by deleting a CH2 group from or adding a CH2 group to the prolyl ring results the remarkable changes in backbone and ring structures compared with those of the Pro dipeptide, especially in the C'-N imide bond length and the bond angles around the N-C(alpha) bond. The four-membered azetidine ring can have either puckered structure depending on the backbone structure because of the less puckered structure. The six-membered piperidine ring can adopt chair and boat conformations, but the chair conformation is more preferred than the boat conformation. These calculated preferences for puckering are consistent with experimental results from analysis of X-ray structures of Aze- and Pip-containing peptides. On going from Pro to Aze to Pip, the axiality (i.e., a tendency to adopt the axial orientation) of the NHMe group becomes stronger, which can be ascribed to reduce the steric hindrances between 1,2-substituted Ac and NHMe groups. As the solvent polarity increases, the polyproline II-like conformation becomes more populated and the relative stability of conformation tC with a C7 hydrogen bond between C'=O of the amino group and N-H of the carboxyl group decreases for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. The cis population and rotational barriers for the imide bond increase with the increase of solvent polarity for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. In particular, the cis-trans isomerization proceeds in common through only the clockwise rotation with omega' approximately +120 degrees about azetyl and piperidyl peptide bonds in the gas phase and in solution, as seen for alanyl and prolyl peptide bonds. The pertinent distance d(N...H-N(NHMe)) and the pyramidality of imide nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure, but the lower rotational barriers for the Aze and Pip dipeptides than those for the Pro dipeptide, which is observed from experiments, cannot be rationalized.     

High-performance liquid chromatographic method for the determination of prolyl peptides in urine

A rapid and accurate method is described for the determination of prolyl peptides in urine, with specific reference to the dipeptide prolylhydroxyproline, and free hydroxyproline and proline. Free amino acids and peptides were isolated from urine on cation-exchange minicolumns, and free imino acids and prolyl-N-terminal peptides were selectively derivatized with 4-chloro-7-nitrobenzofurazan, after reaction of amino acids and N-terminal aminoacyl peptides with o-phthalaldehyde. The highly fluorescent adducts of imino acids and prolyl peptides were separated on a Spherisorb ODS 2 column by isocratic elution for 12 min using as mobile phase 17.5 mM aqueous trifluoracetic acid solution containing 12.5% acetonitrile (eluent A), followed by gradient elution from eluent A to 40% of 17.5 mM aqueous trifluoroacetic acid solution containing 80% acetonitrile in 20 min. Analytes of interest, in particular the dipeptide prolylhydroxyproline, can be easily quantified by fluorimetric detection (epsilon ex = 470 nm, epsilon em = 530 nm) without interference from primary amino-containing compounds.     

Exploiting an inherent neighboring group effect of alpha-amino acids to synthesize extremely hindered dipeptides

The creation of highly hindered peptides that contain combinations of non-natural N-alkyl amino acids and N-alkyl-alpha,alpha-disubstituted amino acids presents a formidable challenge. Hindered, non-natural amino acids are of interest because they import resistance to proteolysis and unusual conformational properties to peptides that contain them. Toward a solution to this problem, we describe a new approach to creating extremely hindered dipeptides that is operationally simple and uses mild conditions and commercially available amino acids. The approach reduces the need for protecting groups and yields urethane-protected dipeptide acids that can be used as building blocks in the synthesis of larger peptides. We propose that the reaction proceeds through a previously unexploited intramolecular O,N-acyl transfer pathway.     

Formation and reactions of clusters in the gas phase: small peptides and carboxylic acids

The cluster formation of seventeen small dipeptides with different primary structures and vanillic acid was investigated by means of a neutral laser desorption and supersonic beam expansion followed by multi photon ionization time of flight mass spectrometry. The structures of these clusters have been characterized by mass spectrometric methods as well as by DFT calculations. It is shown that the structure of the cluster from a dipeptide and vanillic acid is described by a hydrogen bond between the phenolic group of the vanillic acid and the N-terminal amino function of the dipeptide. The intensity of the cluster ion and the main fragmentation product, the protonated peptide ion, can be linked to the proton affinity of the peptide. Furthermore the fragmentation reactions of the protonated peptide are accompanied by extensive hydrogen rearrangements yielding both a and y fragments. The intensities of these fragments follow the proton affinity of the dipeptide.     

Reactions of an aromatic σ,σ-biradical with amino acids and dipeptides in the gas phase

Gas-phase reactivity of a positively charged aromatic σ,σ-biradical (N-methyl-6,8-didehydroquinolinium) was examined toward six aliphatic amino acids and 15 dipeptides by using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR) and laser-induced acoustic desorption (LIAD). While previous studies have revealed that H-atom and NH₂ abstractions dominate the reactions of related monoradicals with aliphatic amino acids and small peptides, several additional, unprecedented reaction pathways were observed for the reactions of the biradical. For amino acids, these are 2H-atom abstraction, H₂O abstraction, addition — CO₂, addition — HCOOH, and formation of a stable adduct. The biradical reacts with aliphatic dipeptides similarly as with aliphatic amino acids, but undergoes also one additional reaction pathway, addition/C-terminal amino acid elimination (addition — CO — NHCHR_C). These reactions are initiated by H-atom abstraction by the biradical from the amino acid or peptide, or nucleophilic addition of an NH₂ or a HO group of the amino acid or peptide at the radical site at C-6 in the biradical. Reactions of the unquenched C-8 radical site then yield the products not observed for related monoradicals. The biradical reacts with aromatic dipeptides with an aromatic ring in N-terminus (i.e., Tyr-Leu, Phe-Val, and Phe-Pro) similarly as with aliphatic dipeptides. However, for those aromatic dipeptides that contain an aromatic ring in the C-terminus (i.e., Leu-Tyr and Ala-Phe), one additional pathway, addition/N-terminal amino acid elimination (addition — CO — NHCHR_N), was observed. This reaction is likely initiated by radical addition of the biradical at the aromatic ring in the C-terminus. Related monoradicals add to aromatic amino acids and small peptides, which is followed by Cα-Cβ bond cleavage, resulting in side-chain abstraction by the radical. For biradicals, with one unquenched radical site after the initial addition, the reaction ultimately results in the loss of the N-terminal amino acid. Similar to monoradicals, the C-S bond in amino acids and dipeptides was found to be especially susceptible to biradical attack.     

Calculations of intermode coupling constants and simulations of amide I,II, and III vibrational spectra of dipeptides

Amide I, II, and III vibrations of polypeptides are important marker modes whose vibrational spectra can provide critical information on structure and dynamics of proteins in solution. The extent of delocalization and vibrational properties of amide normal mode can be described by the amide local mode frequencies and intermode coupling constants between a pair of amide local modes. To determine these fundamental quantities, the previous Hessian matrix reconstruction method has been generalized here and applied to the density functional theory results for various dipeptide conformers. The calculation results are then used to simulate IR absorption, vibrational circular dichroism, and 2D IR spectra of dipeptides. The relationships between dipeptide backbone conformations and these vibrational spectra are discussed. It is believed that the present computational method and results will be of use to quantitatively simulate vibrational spectra of complicated polypeptides beyond simple dipeptides     

A genetic algorithm encoded with the structural information of amino acids and dipeptides for efficient conformational searches of oligopeptides

The genetic algorithm (GA) is an intelligent approach for finding minima in a highly dimensional parametric space. However, the success of GA searches for low energy conformations of biomolecules is rather limited so far. Herein an improved GA scheme is proposed for the conformational search of oligopeptides. A systematic analysis of the backbone dihedral angles of conformations of amino acids (AAs) and dipeptides is performed. The structural information is used to design a new encoding scheme to improve the efficiency of GA search. Local geometry optimizations based on the energy calculations by the density functional theory are employed to safeguard the quality and reliability of the GA structures. The GA scheme is applied to the conformational searches of Lys, Arg, Met‐Gly, Lys‐Gly, and Phe‐Gly‐Gly representative of AAs, dipeptides, and tripeptides with complicated side chains. Comparison with the best literature results shows that the new GA method is both highly efficient and reliable by providing the most complete set of the low energy conformations. Moreover, the computational cost of the GA method increases only moderately with the complexity of the molecule. The GA scheme is valuable for the study of the conformations and properties of oligopeptides. © 2016 Wiley Periodicals, Inc.     

Reactivity of Tyr–Leu and Leu–Tyr dipeptides: identification of oxidation products by liquid chromatography–tandem mass spectrometry

The exposure of peptides and proteins to reactive hydroxyl radicals results in covalent modifications of amino acid side‐chains and protein backbone. In this study we have investigated the oxidation the isomeric peptides tyrosine–leucine (YL) and leucine–tyrosine (LY), by the hydroxyl radical formed under Fenton reaction (Fe²⁺/H₂O₂). Through mass spectrometry (MS), high‐performance liquid chromatography (HPLC‐MS) and electrospray tandem mass spectrometry (HPLC‐MSⁿ) measurements, we have identified and characterized the oxidation products of these two dipeptides. This approach allowed observing and identifying a wide variety of oxidation products, including isomeric forms of the oxidized dipeptides. We detected oxidation products with 1, 2, 3 and 4 oxygen atoms for both peptides; however, oxidation products with 5 oxygen atoms were only present in LY. LY dipeptide oxidation leads to more isomers with 1 and 2 oxygen atoms than YL (3 vs 5 and 4 vs 5, respectively). Formation of the peroxy group occurred preferentially in the C‐terminal residue. We have also detected oxidation products with double bonds or keto groups, dimers (YL–YL and LY–LY) and other products as a result of cross‐linking. Both amino acids in the dipeptides were oxidized although the peptides showed different oxidation products. Also, amino acid residues have shown different oxidation products depending on the relative position on the dipeptide. Results suggest that amino acids in the C‐terminal position are more prone to oxidation. Copyright © 2009 John Wiley & Sons, Ltd.     

Helix formation in alpha,gamma- and beta,gamma-hybrid peptides: theoretical insights into mimicry of alpha- and beta-peptides

Alpha,gamma- and beta,gamma-hybrid peptides, which are composed of two different homologous amino acid constituents in alternate order, are suggested as novel classes of peptide foldamers. On the basis of a systematic conformational search employing the methods of ab initio MO theory, the possibilities for the formation of periodic secondary structures in these systems are described. The conformational analysis provides a great number of helix conformers widely differing in energy, which can be arranged into three groups: (i) helices with all hydrogen bonds formed in forward direction along the sequence, (ii) helices with all hydrogen bonds in backward direction, and (iii) helices with alternate hydrogen-bond directions (mixed or beta-helices). Most stable are representatives of beta-helices, but their stability decreases considerably in more polar environments in comparison to helix conformers from the other two classes. There is a great similarity between the overall topology of the most stable hybrid peptide helices and typical helices of peptides which are exclusively composed of a single type of homologous amino acids. Thus, the helices of the beta,gamma-hybrid peptides mimic perfectly those of the native alpha-peptides as, for instance, the well-known alpha-helix, whereas the most stable helix conformers of alpha,gamma-hybrid peptides correspond well to the overall structure of beta-peptide helices. The two suggested novel hybrid peptide classes expand considerably the pool of peptide foldamers and may be promising tools in peptide design and in material sciences.     

Ab initio calculations on blocked Pro-Ala dipeptides

The effect of the chirality of the amino acid at position i + 2 on a β-turn was investigated by a grid scan ab initio calculation on the Ac- -Pro- -Ala-NH₂ and Ac- -Pro- -Ala-NH₂ blocked dipeptides. Th6-31G basis set was used to estimate the effect of the alanyl side chain on the conformation of the peptide backbone in a blocked dipeptide as a simple, but complete model for a reverse turn. This study provides a quantum mechanical evaluation of the ability of the NH at the i + 3 residue to form the H-bond that closes the 10 membered ring which stabilizes the turn. The lowest energy of all 64 probed conformations of the -Ala containing peptide corresponded to a good type II β-turn with a hydrogen bond distance between the acetyl oxygen and the amide terminal hydrogen of 2.21 Å. A comparison with the nonblocked dipeptide ab initio study indicates that the presence of the end blocks enhances the propensity of the -Ala-containing dipeptide for a type II β-turn, but does not seem to enhance the propensity of the -Ala-containing dipeptide for a type I β-turn. The energies and geometric parameters for the lowest four optimized conformations identified by the grid scan search for each molecule have been calculated.     

The carbenoid approach to peptide synthesis

A different approach to the synthesis of dipeptides is described based on the formation of the NHCHR1CONH-CHR2CO bond by carbenoid N-H insertion, rather than the formation of the peptide bond itself. Thus decomposition of triethyl diazophosphonoacetate catalysed by rhodium(II) acetate in the presence of N-protected amino acid amides 8 gives the phosphonates 9. Subsequent Wadsworth-Emmons reaction of 9 with aldehydes in the presence of DBU gives dehydro dipeptides 10. The reaction has been extended to a simple two-step procedure, without the isolation of the intermediate phosphonate, for conversion of a range of amino acid amides 11 into dehydro dipeptides 12 and to an N-methylamide 11 h, and for conversion of a dipeptide to tripeptide (13-->14). Direct conversion, by using methyl diazophenylacetate, of amino acid amides to phenylglycine-containing dipeptides 19 proceeds in good chemical yield, but with poor diastereoselectivity.     

Head-to-backbone cyclization of peptides on solid support by nucleophilic aromatic substitution

A new versatile synthetic route is presented for the cyclization of tripeptides on solid support using nucleophilic aromatic substitution in the cyclization step. Identification of all conformers within a limit of 3 kcal/mol from the identified global minimum conformations by Monte Carlo conformational searching reveals that five out of six synthesized compounds have well-defined peptide backbone conformational properties. This was determined by clustering the identified conformers against a filter of seven to nine torsion angles in the peptide backbone. Thus, the results meet our goal to find synthetic routes to peptides that are conformationally sufficiently locked to serve as convenient leads for further development of pharmacophoric models. The strategy is based on Fmoc-peptide chemistry on a N-aminoethyl-substituted glycine bound to the commercially available Rink amide PS-resin. After deprotection of the N-terminus of the tripeptide, it is acylated with a fluoronitrobenzoic acid. Subsequently, a Boc group on the N-bound aminoethyl substituent is selectively deprotected allowing cyclization from the head (N-terminus) to the backbone substituent, thereby leading to the desired cyclized tripeptides. A number of representative examples of peptides cyclized by this method have been synthesized and characterized by NMR. Protecting groups that allow the incorporation of side chain functionalized amino acids have been found. Thus, the route provides access to generic libraries of conformationally restricted peptide sequences expressing a range of proteinogenic pharmacophores.     

Conformational preferences of pseudoproline residues

The conformational study on N-acetyl-N'-methylamides of oxazolidine and thiazolidine residues (Ac-Oxa-NHMe and Ac-Thz-NHMe) is carried out using ab initio HF and density functional B3LYP methods with the self-consistent reaction field method to explore the effects of the replacement of the C(gamma)H(2) group in the prolyl ring by oxygen or sulfur atoms on the conformational preferences and prolyl cis-trans isomerization in the gas phase and in solution (chloroform and water). As the solvent polarity increases, the conformations C with the C7 intramolecular hydrogen bonds become depopulated, the PPII- or PPI-like conformations F become more populated, and the cis populations increase for both Oxa and Thz dipeptides, as found for the Pro dipeptide, although the populations of backbone conformations and puckerings are different in pseudoproline and proline dipeptides. As the increase of solvent polarity, the populations of the trans/up conformations decrease for Oxa and Thz dipeptides, but they increase for the Pro dipeptide. It is found that the cis-trans isomerization proceeds through the anticlockwise rotation with omega' approximately -60 degrees about the oxazolidyl peptide bond and the clockwise rotation with omega' approximately +120 degrees about the thiazolidyl peptide bond in the gas phase and in solution, whereas the clockwise rotation is preferred for the prolyl peptide bond. The pertinent distance d(N...H-N(NHMe)) and the pyramidality of the prolyl nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure but the lower rotational barriers for Oxa and Thz dipeptides than those for the Pro dipeptide, which is observed from experiments, cannot be rationalized. The calculated cis populations and rotational barriers to the cis-trans isomerization for both Oxa and Thz dipeptides in chloroform and/or water are consistent with the experimental values.     

298.15 K甘氨酰二肽在乙酸钠水溶液中的体积性质

测定了298.15 K三种甘氨酰二肽(甘氨酰甘氨酸、甘氨酰-L-缬氨酸和甘氨酰-L-亮氨酸)在0.5, 1.0, 1.5和2.0 mol•kg－1乙酸钠水溶液中的密度, 计算了这些肽在乙酸钠水溶液中的表观摩尔体积, 标准偏摩尔体积, 标准偏摩尔转移体积, 理论水化数和体积相互作用参数. 结果表明: 甘氨酰二肽的标准偏摩尔体积和标准偏摩尔转移体积均随乙酸钠浓度的增加而增大, 溶液中离子与肽带电基团/甘氨酰基团(CH2CONH)之间的相互作用大于离子与肽的非极性基团间的相互作用, 乙酸钠和甘氨酰二肽之间主要是对相互作用. 利用共球交盖模型对所研究的肽与乙酸钠之间的体积相互作用进行了解释. 利用氨基酸的标准偏摩尔体积值, 对二肽的标准偏摩尔体积进行了估算, 发现计算值与实验值一致.     

The SAAP force field: Development of the single amino acid potentials for 20 proteinogenic amino acids and Monte Carlo molecular simulation for short peptides

Molecular simulation by using force field parameters has been widely applied in the fields of peptide and protein research for various purposes. We recently proposed a new all‐atom protein force field, called the SAAP force field, which utilizes single amino acid potentials (SAAPs) as the fundamental elements. In this article, whole sets of the SAAP force field parameters in vacuo, in ether, and in water have been developed by ab initio calculation for all 20 proteinogenic amino acids and applied to Monte Carlo molecular simulation for two short peptides. The side‐chain separation approximation method was employed to obtain the SAAP parameters for the amino acids with a long side chain. Monte Carlo simulation for Met‐enkephalin (CHO‐Tyr‐Gly‐Gly‐Phe‐Met‐NH₂) by using the SAAP force field revealed that the conformation in vacuo is mainly controlled by strong electrostatic interactions between the amino acid residues, while the SAAPs and the interamino acid Lennard‐Jones potentials are predominant in water. In ether, the conformation would be determined by the combination of the three components. On the other hand, the SAAP simulation for chignolin (H‐Gly‐Tyr‐Asp‐Pro‐Glu‐Thr‐Gly‐Thr‐Trp‐Gly‐OH) reasonably reproduced a native‐like β‐hairpin structure in water although the C‐terminal and side‐chain conformations were different from the native ones. It was suggested that the SAAP force field is a useful tool for analyzing conformations of polypeptides in terms of intrinsic conformational propensities of the single amino acid units. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

A fast method for large‐scale De Novo peptide and miniprotein structure prediction

Although peptides have many biological and biomedical implications, an accurate method predicting their equilibrium structural ensembles from amino acid sequences and suitable for large‐scale experiments is still missing. We introduce a new approach—PEP‐FOLD—to the de novo prediction of peptides and miniproteins. It first predicts, in the terms of a Hidden Markov Model‐derived structural alphabet, a limited number of local conformations at each position of the structure. It then performs their assembly using a greedy procedure driven by a coarse‐grained energy score. On a benchmark of 52 peptides with 9–23 amino acids, PEP‐FOLD generates lowest‐energy conformations within 2.8 and 2.3 Å Cα root‐mean‐square deviation from the full nuclear magnetic resonance structures (NMR) and the NMR rigid cores, respectively, outperforming previous approaches. For 13 miniproteins with 27–49 amino acids, PEP‐FOLD reaches an accuracy of 3.6 and 4.6 Å Cα root‐mean‐square deviation for the most‐native and lowest‐energy conformations, using the nonflexible regions identified by NMR. PEP‐FOLD simulations are fast—a few minutes only—opening therefore, the door to in silico large‐scale rational design of new bioactive peptides and miniproteins. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010