Influence of chirality of the preceding acyl moiety on the cis/trans ratio of the proline peptide bond

We report that the cis/trans ratio of the proline peptide bond can be strongly influenced by the chirality of the acyl residue preceding proline. Acyl moieties derived from (2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) in acyl-Pro molecules influence isomerization of the proline peptide bond constraining the omega dihedral angle to the trans orientation. Structures of benzyl (2S)-1-([(2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl)-2-pyrrolidinecarboxylate (3) derived from 2D (1)H NMR conformational analysis and crystallographic data exhibit only the trans conformation of proline peptide bond. On the other hand the diastereomer 4, which contains an (R) acyl moiety, exhibits two sets of signals in (1)H NMR spectra. The signals were assigned to trans (72%) and cis (28%) conformers. Crystallographic analysis of 4 showed that only the cis conformation is present in the crystalline state. The (1)H NMR chemical shift pattern of three sets of signals observed in 2 was observed also in benzyl (2S)-1-[(2R/S)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate. (R)-Carboxylic acid 5, after coupling with (S)-ProOBn, yielded benzyl (2S)-1-[(2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate (6), which in DMSO-d(6) exhibited only the trans conformation of the proline peptide bond. These results suggest that in these particular cases acyl-Pro peptide bond isomerization is strongly influenced by the stereochemistry of the acyl residue preceding proline. (2S)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) are promising chiral peptidomimetic building blocks that can be used as acyl moieties to force the proline peptide bond into the trans conformation in a variety of acyl-Pro molecules.     

Kinetics and equilibria of cis/trans isomerization of backbone amide bonds in peptoids

The biological activities of N-substituted glycine oligomers (peptoids) have been the subject of extensive research. As compared to peptides, both the cis and trans conformations of the backbone amide bonds of peptoids can be significantly populated. Thus, peptoids are mixtures of configurational isomers, with the number of isomers increasing by a factor of 2 with each additional monomer residue. Here we report the results of a study of the kinetics and equilibria of cis/trans isomerization of the amide bonds of N-acetylated peptoid monomers, dipeptoids, and tripeptoids by NMR spectroscopy. Resonance intensities indicate the cis conformation of the backbone amide bonds of the peptoids studied is more populated than is generally the case for the analogous secondary amide bond to proline residues in acyclic peptides. Rate constants were measured by inversion-magnetization transfer techniques over a range of temperatures, and activation parameters were derived from the temperature dependence of the rate constants. The rate of cis/trans isomerization by rotation around the amide bonds in the peptoids studied is generally slower than that around amide bonds to proline residues and takes place on the NMR inversion-magnetization transfer time scale only by rotation around the amide bond to the C-terminal peptoid residue.     

Conformational preferences of non-prolyl and prolyl residues

The conformational study on Ac-Ala-NHMe (the alanine dipeptide) and Ac-Pro-NHMe (the proline dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the differences in the backbone conformational preference and the cis-trans isomerization for the non-prolyl and prolyl residues in the gas phase and in the solutions (chloroform and water). For the alanine and proline dipeptides, with the increase of solvent polarity, the populations of the conformation tC with an intramolecular C(7) hydrogen bond significantly decrease, and those of the polyproline II-like conformation tF and the alpha-helical conformation tA increase, which is in good agreement with the results from circular dichroism and NMR experiments. For both the dipeptides, as the solvent polarity increases, the relative free energy of the cis conformer to the trans conformer decreases and the rotational barrier to the cis-trans isomerization increases. It is found that the cis-trans isomerization proceeds in common through only the clockwise rotation with omega' approximately +120 degrees about the non-prolyl and prolyl peptide bonds in both the gas phase and the solutions. The pertinent distance d(N...H-N(NHMe)) can successfully describe the increase in the rotational barriers for the non-prolyl and prolyl trans-cis isomerization as the solvent polarity increases and the higher barriers for the non-prolyl residue than for the prolyl residue, as seen in experimental and calculated results. By analysis of the contributions to rotational barriers, the cis-trans isomerization for the non-prolyl and prolyl peptide bonds is proven to be entirely enthalpy driven in the gas phase and in the solutions. The calculated cis populations and rotational barriers to the cis-trans isomerization for both the dipeptides in chloroform and/or water accord with the experimental values.     

First-principle computational study on the full conformational space of L-threonine diamide, the energetic stability of cis and trans isomers

First-principle computations were carried out on the conformational space of trans and cis peptide bond isomers of HCO-Thr-NH2. Using the concept of multidimensional conformational analysis (MDCA), geometry optimizations were performed at the B3LYP/6-31G(d) level of theory, and single-point energies as well as thermodynamic functions were calculated at the G3MP2B3 level of theory for the corresponding optimized structures. Two backbone Ramachandran-type potential energy surfaces (PESs) were computed, one each for the cis and trans isomers, keeping the side chain at the fully extended orientation (chi1=chi2=anti). Similarly, two side chain PESs for the cis and trans isomers were generated for the (phi=psi=anti) orientation corresponding to approximately the betaL backbone conformation. Besides correlating the relative Gibbs free energy of the various stable conformations with the number of stabilizing hydrogen bonds, the process of trans-->cis isomerization is discussed in terms of intrinsic stabilities as measured by the computed thermodynamic functions.     

4-Methylpseudoproline derived from α-methylserine - synthesis and conformational studies

This paper presents the synthesis and solution conformational studies of the tripeptides Fmoc-Ala-(R)-(αMe)Ser(Ψ(H,H)Pro)-Ala-OBu(t) (6a) and Fmoc-Ala-(S)-(αMe)Ser(Ψ(H,H)Pro)-Ala-OBu(t) (6b). Additionally, the X-ray structure of 6a is given. NMR analysis corroborated by theoretical calculations (XPLOR) shows that in both peptides the amide bond between pseudoproline and the preceding amino acid is in the trans conformation. The same amide bond geometry was observed in the crystal state of 6a. The latter is additionally influenced by the presence of two symmetrically independent molecules in an asymmetric unit. Both molecules adopt a conformation which resembles β-turn type II, stabilized by hydrogen bonding. The conformational preferences and prolyl cis-trans isomerization of Ac-(αMe)Ser(Ψ(H,H)Pro)-NHMe (7) were explored at the IEFPCM/B3LYP/6-31+G(d) level of theory in vacuum, water and chloroform. It has been shown that the trans isomer predominates in water solutions and the cis isomer is preferred in chloroform. The conformation of 7 is down-puckered independently of the geometry of the amide bonds, with lower puckering in the transition state of the cis-trans isomerization.     

Conformational preferences and cis-trans isomerization of azaproline residue

The conformational study of N-acetyl-N'-methylamide of azaproline (Ac-azPro-NHMe, the azPro dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the effects of the replacement of the backbone CHalpha group by the nitrogen atom on the conformational preferences and prolyl cis-trans isomerization in the gas phase and in solution (chloroform and water). The incorporation of the Nalpha atom into the prolyl ring results in the different puckering, backbone population, and barriers to prolyl cis-trans isomerization from those of Ac-Pro-NHMe (the Pro dipeptide). In particular, the azPro dipeptide has a dominant backbone conformation D (beta2) with the cis peptide bond preceding the azPro residue in both the gas phase and solution. This may be ascribed to the favorable electrostatic interaction or intramolecular hydrogen bond between the prolyl nitrogen and the amide hydrogen following the azPro residue and to the absence of the unfavorable interactions between electron lone pairs of the acetyl carbonyl oxygen and the prolyl Nalpha. This calculated higher population of the cis peptide bond is consistent with the results from X-ray and NMR experiments. As the solvent polarity increases, the conformations B and B* with the trans peptide bond become more populated and the cis population decreases more, which is opposite to the results for the Pro dipeptide. The conformation B lies between conformations D and A (alpha) and conformation B* is a mirror image of the conformation B on the phi-psi map. The barriers to prolyl cis-trans isomerization for the azPro dipeptide increase with the increase of solvent polarity, and the cis-trans isomerization proceeds through only the clockwise rotation with omega' approximately +120 degrees about the prolyl peptide bond for the azPro dipeptide in the gas phase and in solution, as seen for the Pro dipeptide. The pertinent distance d(N...H-NNHMe) and the pyramidality of imide nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure and the lower rotational barriers for the azPro dipeptide than those for the Pro dipeptide in the gas phase and in solution.     

A fast photoswitch for minimally perturbed peptides: investigation of the trans-->cis photoisomerization of N-methylthioacetamide

Thio amino acids can be integrated into the backbone of peptides without significantly perturbing their structure. In this contribution we use ultrafast infrared and visible spectroscopy as well as state-of-the-art ab initio computations to investigate the photoisomerization of the trans form of N-methylthioacetamide (NMTAA) as a model conformational photoswitch. Following the S2 excitation of trans-NMTAA in water, the return of the molecule into the trans ground state and the formation of the cis isomer is observed on a dual time scale, with a fast component of 8-9 ps and a slow time constant of approximately 250 ps. On both time scales the probability of isomerization to the cis form is found to be 30-40%, independently of excitation wavelength. Ab initio CASPT2//CASSCF photochemical reaction path calculations indicate that, in vacuo, the trans-->cis isomerization event takes place on the S1 and/or T1 triplet potential energy surfaces and is controlled by very small energy barriers, in agreement with the experimentally observed picosecond time scale. Furthermore, the calculations identify one S2/S1 and four nearly isoenergetic S1/S0 conical intersection decay channels. In line with the observed isomerization probability, only one of the S1/S0 conical intersections yields the cis conformation upon S1-->S0 decay. A substantially equivalent excited-state relaxation results from four T1/S0 intersystem crossing points.     

The impact of pyrrolidine hydroxylation on the conformation of proline-containing peptides

[structure: see text] A series of eight dipeptides of the general formula Ac-Phe-Pro-NHMe was synthesized and the thermodynamics of the cis --> trans isomerization about the central amide bond were studied by NMR. Pro* represents the following prolines: l-proline (Pro), l-trans-4-hydroxyproline (Hyp), l-cis-4-hydroxyproline (hyp), l-cis-4-methoxyproline (hyp[OMe]), l-trans-3-hydroxyproline (3-Hyp), l-cis-3-hydroxyproline (3-hyp), l-2,3-trans-3,4-cis-3,4-dihydroxyproline (DHP), and l-2,3-cis-3,4-trans-3,4-dihydroxyproline (dhp). The conformation of the pyrrolidine ring in each case is discussed in light of previous structural studies, analysis of potential stereoelectronic effects, and NMR data. Hydroxy substituents at C-4 have a greater impact on cis --> trans isomerization than analogous substituents at C-3 as a result of the intervening bond distances and bridging groups. The position of the equilibrium and its dependence on temperature are a reflection of both enthalpic and entropic factors, the latter being complicated in this study by an Ar-Pro interaction in the cis conformation. The substituents on the pyrrolidine ring determine the conformation of the five-membered ring, which in turn influences the strength of the Ar-Pro interaction, backbone dihedral angles, and the relative energy of the cis and trans species. The ultimate position of the equilibrium depends on a complex blend of steric, electronic, and conformational factors.     

Collagen stability: insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations

Collagen-like peptides of the type (Pro-Pro-Gly)(10) fold into stable triple helices. An electron-withdrawing substituent at the H(gamma)(3) ring position of the second proline residue stabilizes these triple helices. The aim of this study was to reveal the structural and energetic origins of this effect. The approach was to obtain experimental NMR data on model systems and to use these results to validate computational chemical analyses of these systems. The most striking effects of an electron-withdrawing substituent are on the ring pucker of the substituted proline (Pro(i)) and on the trans/cis ratio of the Xaa(i-1)-Pro(i) peptide bond. NMR experiments demonstrated that N-acetylproline methyl ester (AcProOMe) exists in both the C(gamma)-endo and C(gamma)-exo conformations (with the endo conformation slightly preferred), N-acetyl-4(R)-fluoroproline methyl ester (Ac-4R-FlpOMe) exists almost exclusively in the C(gamma)-exo conformation, and N-acetyl-4(S)-fluoroproline methyl ester (Ac-4S-FlpOMe) exists almost exclusively in the C(gamma)-endo conformation. In dioxane, the K(trans/cis) values for AcProOMe, Ac-4R-FlpOMe, and Ac-4S-FlpOMe are 3.0, 4.0, and 1.2, respectively. Density functional theory (DFT) calculations with the (hybrid) B3LYP method were in good agreement with the experimental data. Computational analysis with the natural bond orbital (NBO) paradigm shows that the pucker preference of the substituted prolyl ring is due to the gauche effect. The backbone torsional angles, phi and psi, were shown to correlate with ring pucker, which in turn correlates with the known phi and psi angles in collagen-like peptides. The difference in K(trans/cis) between AcProOMe and Ac-4R-FlpOMe is due to an n-->pi interaction associated with the Bürg-Dunitz trajectory. The decrease in K(trans/cis) for Ac-4S-FlpOMe can be explained by destabilization of the trans isomer because of unfavorable electronic and steric interactions. Analysis of the results herein along with the structures of collagen-like peptides has led to a theory that links collagen stability to the interplay between the pyrrolidine ring pucker, phi and psi torsional angles, and peptide bond trans/cis ratio of substituted proline residues.     

Enol-to-keto tautomerism of peptide groups

Density functional based simulations, performed on polyglycine containing an enol peptide group [-C(OH)N-] which is a structural isomer of a keto form [-CONH-], show that in the enol-to-keto tautomeric reaction, the enol peptide group is less stable than the keto form, and that the enol-to-keto tautomerism is characterized by a cis/trans isomerization of the C-N peptide bond. The rate-limiting step in the cis/trans isomerization is a hydrogen migration from O to N atoms in the peptide group with a transition state consisting of a four-membered ring in the cis configuration. An analysis of the cis/trans isomerization pathway shows that the mechanisms for the cis/trans isomerization are essentially different between the enol and keto forms.     

Conformational profile of a proline-arginine hybrid

The intrinsic conformational preferences of a new nonproteinogenic amino acid have been explored by computational methods. This tailored molecule, named ((β)Pro)Arg, is conceived as a replacement for arginine in bioactive peptides when the stabilization of folded turn-like conformations is required. The new residue features a proline skeleton that bears the guanidilated side chain of arginine at the C(β) position of the five-membered pyrrolidine ring, in either a cis or a trans orientation with respect to the carboxylic acid. The conformational profiles of the N-acetyl-N'-methylamide derivatives of the cis and trans isomers of ((β)Pro)Arg have been examined in the gas phase and in solution by B3LYP/6-31+G(d,p) calculations and molecular dynamics simulations. The main conformational features of both isomers represent a balance between geometric restrictions imposed by the five-membered pyrrolidine ring and the ability of the guanidilated side chain to interact with the backbone through hydrogen bonds. Thus, both cis- and trans-((β)Pro)Arg exhibit a preference for the α(L) conformation as a consequence of the interactions established between the guanidinium moiety and the main-chain amide groups.     

Conformational preferences and cis-trans isomerization of L-lactic acid residue

The conformational study on N-acetyl- N'-methylamide of l-lactic acid (Ac-Lac-NHMe, the Lac dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore its backbone conformational preferences and cis-trans isomerization for the depsipeptide with an ester bond in the gas phase and in solution. In the gas phase and in chloroform, the conformation tB with a trans depsipeptide bond is most preferred for the Lac dipeptide, whose backbone torsion angles are phi approximately -150 degrees and psi approximately -5 degrees , juxtaposed to those of the 3 10-helical structure. The larger shift in phi is brought to reduce the repulsion between the two carbonyl carbons of the acetyl and NHMe groups. However, the polyproline II-like tF conformation becomes more populated and the relative stability of conformation tB decreases significantly as the solvent polarity increases. This may be ascribed to weakening a C(5) hydrogen bond between the depsipeptidyl oxygen and the carboxyl amide hydrogen that plays a role in stabilizing the conformation tB in the gas phase and in chloroform. The cis populations about the depsipeptide bond are nearly negligible in the gas phase and in solution. The rotational barriers to the cis-trans isomerization of the depsipeptide bond for the Lac dipeptide are calculated to be about 11 kcal/mol, which is about half of those for the Ala dipeptide, although they increase somewhat with the increase of solvent polarity. The cis-trans isomerization of the depsipeptide bond proceeds through either clockwise or anticlockwise rotations with torsion angles of about +90 degrees or -90 degrees , respectively, in the gas phase and in solution, whereas it has been known that the isomerization proceeds through only the clockwise rotation for alanyl and prolyl peptide bonds. The pertinent distances between the depsipeptidyl oxygen and the carboxyl amide hydrogen can describe the role of this hydrogen bond in stabilizing the transition state structures in the gas phase and in solution.     

Diphtheria toxin catalyzed hydrolysis of NAD(+): molecular dynamics study of enzyme-bound substrate, transition state, and inhibitor.

The mechanism of the diphtheria toxin-catalyzed hydrolysis of NAD(+) was investigated by quantum chemical calculations and molecular dynamics simulations. Several effects that could explain the 6000-fold rate acceleration (Delta Delta G(++) approximately 5 kcal/mol) by the enzyme were considered. First, the carboxamide arm of the enzyme-bound NAD(+) adopts a trans conformation while the most stable conformation is cis. The most stable conformation for the nicotinamide product has the amide carbonyl trans. The activation energy for the cleavage of the ribosidic bond is reduced by 2 kcal/mol due to the relaxation of this ground state conformational stress in the transition state. Second, molecular dynamics simulations to the nanosecond time range revealed that the carboxylate of Glu148 forms a hydrogen bond to the substrate's 2' hydroxyl group in E.S (approximately 17% of the time) and E.TS (approximately 57% of the time) complexes. This interaction is not seen in crystal structures. The ApUp inhibitor is held more tightly by the enzyme than the transition state and the substrate. Analysis of correlated motions reveals differences in the pattern of anticorrelated motions for protein backbone atoms when the transition state occupies the active site as compared to the E.NAD(+) complex.     

Quantum mechanical study of the conformational behavior of proline and 4R-hydroxyproline dipeptide analogues in vacuum and in aqueous solution

The conformational behavior of the title compounds has been investigated by Hartree-Fock, MP2, and DFT computations on the most significant structures related to variations of the backbone dihedral angles, cis/trans isomerism around the peptide bond, and diastereoisomeric puckering of the pyrrolidine ring. In vacuum the reversed gamma turn (gammal), characterized by an intramolecular hydrogen bridge, corresponds to the absolute energy minimum for both puckerings (up and down) of the pyrrolidine ring. An additional energy minimum is found in the helix region, but only for an up puckering of the pyrrolidine ring. When solvent effects are included by means of the polarizable continuum model the conformer observed experimentally in condensed phases becomes the absolute minimum. The down puckering is always favored over its up counterpart, albeit by different amounts (0.4-0.5 kcal/mol for helical structures and about 2 kcal/mol for gammal structures). In helical structures cis arrangements of the peptide bond are only slightly less stable than their trans counterparts. This is no longer true for gammal structures, because the formation of an intramolecular hydrogen bond is possible only for trans peptide bonds. In most cases, proline and hydroxyproline show the same general trends; however, the electronegative 4(R) substituent of hydroxyproline leads to a strong preference for up puckerings irrespective of the backbone conformation.     

Probing highly efficient photoisomerization of a bridged azobenzene by a combination of CASPT2//CASSCF calculation with semiclassical dynamics simulation

Mechanism of phototriggered isomerization of azobenzene and its derivatives is of broad interest. In this paper, the S(0) and S(1) potential energy surfaces of the ethylene-bridged azobenzene (1) that was recently reported to have highly efficient photoisomerization were determined by ab initio electronic structure calculations at different levels and further investigated by a semiclassical dynamics simulation. Unlike azobenzene, the cis isomer of 1 was found to be more stable than the trans isomer, consistent with the experimental observation. The thermal isomerization between cis and trans isomers proceeds via an inversion mechanism with a high barrier. Interestingly, only one minimum-energy conical intersection was determined between the S(0) and S(1) states (CI) for both cis → trans and trans → cis photoisomerization processes and confirmed to act as the S(1) → S(0) decay funnel. The S(1) state lifetime is ～30 fs for the trans isomer, while that for the cis isomer is much longer, due to a redistribution of the initial excitation energies. The S(1) relaxation dynamics investigated here provides a good account for the higher efficiency observed experimentally for the trans → cis photoisomerization than the reverse process. Once the system decays to the S(0) state via CI, formation of the trans product occurs as the downhill motion on the S(0) surface, while formation of the cis isomer needs to overcome small barriers on the pathways of the azo-moiety isomerization and rotation of the phenyl ring. These features support the larger experimental quantum yield for the cis → trans photoisomerization than the trans → cis process.     

Conformational preferences of beta- and gamma-aminated proline analogues

Quantum mechanical calculations have been used to investigate how the incorporation of an amino group to the Cbeta- or Cgamma-positions of the pyrrolidine ring affects the intrinsic conformational properties of the proline. Specifically, a conformational study of the N-acetyl-N'-methylamide derivatives of four isomers of aminoproline, which differ not only in the beta- or gamma-position of the substituent but also in its cis or trans relative disposition, has been performed. To further understand the role of the intramolecular hydrogen bonds between the backbone carbonyl groups and the amino side group, a conformational study was also performed on the corresponding four analogues of (dimethylamino)proline. In addition, the effects of solvation on aminoproline and (dimethylamino)proline dipeptides have been evaluated using a self-consistent reaction field model, and considering four different solvents (carbon tetrachloride, chloroform, methanol and water). Results indicate that the incorporation of the amino substituent into the pyrrolidine ring affects the conformational properties, with backbone...side chain intramolecular hydrogen bonds detected when it is incorporated in a cis relative disposition. In general, the incorporation of the amino side group tends to stabilize those structures where the peptide bond involving the pyrrolidine nitrogen is arranged in cis. The aminoproline isomer with the substituent attached to the Cgamma-position with a cis relative disposition is the most stable in the gas phase and in chloroform, methanol and water solutions. Replacement of the amino side group by the dimethylamino substituent produces significant changes in the potential energy surfaces of the four investigated (dimethylamino)proline-containing dipeptides. Thus, these changes affect not only the number of minima, which increases considerably, but also the backbone and pseudorotational preferences. In spite of these effects, comparison of the conformational preferences, i.e., the more favored conformers, calculated for different isomers of aminoproline and (dimethylamino)proline dipeptides showed a high degree of consistency for the two families of compounds.     

Conformational analysis of dehydrodidemnin B (aplidine) by NMR spectroscopy and molecular mechanics/dynamics calculations.

Dehydrodidemnin B (DDB or aplidine), a potent antitumoral natural product currently in phase II clinical trials, exists as an approximately 1:1 mixture of two slowly interconverting conformations. These are sufficiently long-lived so as to allow their resolution by HPLC. NMR spectroscopy shows that this phenomenon is a consequence of restricted rotation about the Pyr-Pro(8) terminal amide bond of the molecule's side chain. The same technique also indicates that the overall three-dimensional structures of both the cis and trans isomers of DDB are similar despite the conformational change. Molecular dynamics simulations with different implicit and explicit solvent models show that the ensembles of three-dimensional structures produced are indeed similar for both the cis and trans isomers. These studies also show that hydrogen bonding patterns in both isomers are alike and that each one is stabilized by a hydrogen bond between the pyruvyl unit at the terminus of the molecule's side chain and the Thr(6) residue situated at the junction betwen the macrocycle and the molecule's side chain. Nevertheless, each conformational isomer forms this hydrogen bond using a different pyruvyl carbonyl group: CO(2) in the case of the cis isomer and CO(1) in the case of the trans isomer.     

PHOTOACOUSTIC CALORIMETRY OF CYCLOHEPTENE DERIVATIVES. RELAXED TRIPLET ENERGIES OF 1-PHENYLCYCLOHEPTENE AND 1, 3-CYCLOHEPTADIENE AND THE ENERGETICS OF GROUND-STATE cis-trans ISOMERIZATION

Abstract— The heat of isomerization E _ct of cis -1-phenylcycloheptene ( c -PC7) to its highly strained trans isomer has been determined by a combination of a quantitative study of acid-catalyzed trapping of the trans isomer with time-resolved photoacoustic calorimetry. The relaxed triplet energy has been determined for PC7 and for cis, cis -1, 3-cycloheptadiene. The triplet energies are in line with previous studies of other alkenes but the E _ct value is significantly higher than that calculated by molecular mechanics calculations for cycloheptene. The significance of the results for cis-trans thermal isomerization is discussed.     

Electronic control of amide cis-trans isomerism via the aromatic-prolyl interaction

The cis-trans isomerization of prolyl amide bonds results in large structural and functional changes in proteins and is a rate-determining step in protein folding. We describe a novel electronic strategy to control cis-trans isomerization, based on the demonstration that interactions between aromatic residues and proline are tunable by aromatic electronics. A series of peptides of sequence TXPN, X = Trp, pyridylalanine, pentafluorophenylalanine, or 4-Z-phenylalanine derivatives (Z = electron-donating, electron-withdrawing, or electron-neutral substituents), was synthesized and Ktrans/cis analyzed by NMR. Electron-rich aromatic residues stabilized cis amide bond formation, while electron-poor aromatics relatively favored trans amide bond formation. A Hammett correlation between aromatic electronics and cis-trans isomerization was observed. These results indicate that the interaction between aromatic residues and proline, which is observed to stabilize cis amide bonds and is also a general stabilizing interaction ubiquitous in proteins and protein-protein complexes, is not stabilized exclusively by a classical hydrophobic effect. To a large extent, the aromatic-prolyl interaction is driven and controllable by an electronic effect between the aromatic ring pi-electrons and the proline ring, consistent with a C-H-pi interaction as the key stabilizing force. The aromatic-prolyl interaction is electronically tunable by 0.9 kcal/mol and is enthalpic in nature. In addition, by combining aromatic ring electronics and stereoelectronic effects using 4-fluoroprolines, we demonstrate broad tuning (2.0 kcal/mol) of cis-trans isomerism in tetrapeptides. We demonstrate a simple tetrapeptide, TWflpN, that exhibits 60% cis amide bond and adopts a type VIa1 beta-turn conformation.     

DNA-based optomechanical molecular motor

An azobenzene-capped DNA hairpin coupled to an AFM is presented as an optically triggered single-molecule motor. The photoinduced trans to cis isomerization of azobenzene affects both the overall length of the molecule and the ability of the DNA bases to hybridize. Using a combination of molecular dynamics simulations and free energy calculations the unfolding of both isomers along the O5'-O3' extension coordinate is monitored. The potentials of mean force (PMFs) along this coordinate indicate that there are two major differences induced by photoisomerization. The first is that the interbase hydrogen bond and stacking interactions are stable for a greater range of extensions in the trans system than in the cis system. The second difference is due to a decreased chain length of the cis isomer with respect to the trans isomer. These differences are exploited to extract work in optomechanical cycles. The disruption of the hairpin structure gives a maximum of 3.4 kcal mol(-1) of extractable work per cycle with an estimated maximum efficiency of 2.4%. Structure-function insights into the operation of this motor are provided, and the effect of the cantilever stiffness on the extractable work is characterized.