Location of proline derivatives in conformational space. I. Conformational calculations; optical activity and NMR experiments.
TL;DR: In order to develop methods of analysis applicable to the determination of the conformation of biological polymers in solution, a series of proline derivatives was studied and qualitative theoretical considerations enabled molecular groups to be located.
Abstract: In order to develop methods of analysis applicable to the determination of the conformation of biological polymers in solution, a series of proline derivatives was studied. The steric constraints of the pyrrolidine ring limit these compounds to a relatively small set of conformations. This set was further reduced by eliminating conformations with large computed conformational energy. Computations revealed that the conformational energy of the proline derivatives fits into one of three classes, depending on the bulk and the polarity of the C-terminal group. Three analogous classes of optical activity were observed. The optical activity data were analyzed in terms of conformations computed to be of low energy. In some cases qualitative theoretical considerations enabled molecular groups to be located. For example, solvent-dependent isomerization of the carboxyl hydrogen of N-acetyl-L-proline was detected. Nuclear magnetic resonance provided an experimental measure of the fraction of molecules which had cis unsymmetrically-substituted tertiary amide groups. This information aided and confirmed the other measures of molecular conformation.
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TL;DR: Since the present model assumes that only one of the major kinetic phases seen in denaturation reactions is concerned with the denaturation process per se, it is in agreement with numerous thermodynamic studies which show consistency with the two-state model for unfolding.
Abstract: A model is proposed to account for the observation that the denaturation of small proteins apparently occurs in two kinetic phases It is suggested that only one of these phases--the fast one--is actually an unfolding process The slow phase is assumed to arise from the cis-trans isomerism of proline residues in the denaturated protein From model compound data, it is shown that the expected rate for isomerism is in satisfactory agreement with the rates actually observed for protein folding It is also shown that a simple model of protein unfolding based on the isomerism concept is very successful in accounting for many known experimental characteristics of the kinetics and thermodynamic of protein denaturation Thus, the model is able to predict that two kinetic phases will be seen in the transition region while none are seen in the base-line regions, that both the fast and slow refolding phases lead to the native protein as the product, that the fast phase becomes the only observable phase for jumps ending far in the denatured base-line region, that most or all small proteins show a limiting low-temperature activation energy of ca 20,000 cal, and that the relaxtion time for the slow phase seen in cytochrome c denaturation is much shorter than for all other small proteins By utilizing "double-jump" experiments, it is shown directly that the slow phase is not part of the unfolding process but that it corresponds to a transition among two or more denatured forms which have identical spectroscopic (2865 nm) properties Thus, the slow relaxation is "invisible" except in the transition region where it couples to the fast unfolding equilibrium Finally, since the present model assumes that only one of the major kinetic phases seen in denaturation reactions is concerned with the denaturation process per se, it is in agreement with numerous thermodynamic studies which show consistency with the two-state model for unfolding
1,072 citations
01 Jan 1974
TL;DR: Aromatic Contributions To Circular Dichroism Spectra Of Protein this paper were discussed in detail in the CRC Critical Reviews in Biochemistry: Vol. 2, No. 1, pp. 113-175.
Abstract: (1974). Aromatic Contributions To Circular Dichroism Spectra Of Protein. CRC Critical Reviews in Biochemistry: Vol. 2, No. 1, pp. 113-175.
657 citations
01 Jan 1980
TL;DR: In this article, reverse turns in Peptides and Protein are discussed and discussed in the context of protein synthesis and protein protein synthesis, and a review of the review is given, with a focus on protein synthesis.
Abstract: (1980). Reverse Turns in Peptides and Protein. Critical Reviews in Biochemistry: Vol. 8, No. 4, pp. 315-399.
437 citations
01 Jan 1980
TL;DR: This review focuses both on model peptides and biological activity polypeptide molecules and on intramolecularly hydrogen-bonded peptide structures involving a side-chain group, the N-protecting group, and a beta-amino acid.
Abstract: (1980). Intramolecularly Hydrogen-Bonded Peptide Conformation. Critical Reviews in Biochemistry: Vol. 9, No. 1, pp. 1-44.
343 citations
TL;DR: It is shown that a proline residue with an N‐formyl group (Hi−1−C′i−1=Oi−2) likewise prefers a trans conformation, and it is proposed that this electronic effect provides substantial stabilization to this and other elements of protein structure.
Abstract: The well-known preference of the peptide bond for the trans conformation has been attributed to steric effects. Here, we show that a proline residue with an N-formyl group (Hi−1−C′i−1=Oi−1), in which Hi−1 presents less steric hindrance than does Oi−1, likewise prefers a trans conformation. Thus, the preference of the peptide bond for the trans conformation cannot be explained by steric effects alone. Rather, an n → π* interaction between the oxygen of the peptide bond (Oi−1), and the subsequent carbonyl carbon in the polypeptide chain (C′i) also contributes to this preference. The Oi−1 and C′i distance and Oi−1···C′i=Oi angle are especially favorable for such an n → π* interaction in a polyproline II helix. We propose that this electronic effect provides substantial stabilization to this and other elements of protein structure.
227 citations
Cites methods from "Location of proline derivatives in ..."
...The synthesis of amide 1 as a methyl ester rather than a secondary amide avoids intramolecular hydrogen bonding to form a -turn, as has been observed in N-acetylproline (Madison and Schellman 1970; DeTar and Luthra 1977) and N-acetylproline N-methylamide (Matsuzaki and Iitaka 1971; Higashijima et al. 1977; Liang et al. 1992; Benzi et al. 2002)....
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...…1 as a methyl ester rather than a secondary amide avoids intramolecular hydrogen bonding to form a -turn, as has been observed in N-acetylproline (Madison and Schellman 1970; DeTar and Luthra 1977) and N-acetylproline N-methylamide (Matsuzaki and Iitaka 1971; Higashijima et al. 1977; Liang et…...
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TL;DR: This chapter considers the parameters that are required for an adequate description of a polypeptide chain and the mathematical method of utilizing these parameters for calculating the coordinates of all the atoms in a suitable frame of reference so that all the interatomic distances, and bond angles, can be calculated and their consequences worked out.
Abstract: Publisher Summary This chapter deals with the recent developments regarding the description and nature of the conformation of proteins and polypeptides with special reference to the stereochemical aspects of the problem. This chapter considers the parameters that are required for an adequate description of a polypeptide chain. This chapter focuses the attention on what may be called “internal parameters”—that is, those which can be defined in terms of the relationships among atoms or units that form the building blocks of the polypeptide chains. This chapter also provides an account of the mathematical method of utilizing these parameters for calculating the coordinates of all the atoms in a suitable frame of reference, so that all the interatomic distances, and bond angles, can be calculated and their consequences worked out. This chapter observes conformations in amino acids, peptides, polypeptides, and proteins.
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Abstract: Energy calculations have been carried out for several isolated (single‐stranded) homopolymer polyamino acids in order to find the most stable regular (helical) conformations. The energy was expressed as a function of the dihedral angels φ, ψ, and the set of χi's, for rotations about the N–Cα and Cα–C′ bonds of the backbone, and the j single bonds of the side chain, respectively. Torsional, nonbonded, hydrogen‐bonded, and dipole—dipole interaction energy contributions were included. For regular structures, the set of φ, ψ, and the χi's is the same in every residue. Energy contours (expressed in kilocalories per mole of monomer) were plotted on ψ‐vs‐φ diagrams at fixed values of the χi's or on χ2‐vs‐χ1 diagrams at fixed φ and ψ (and, in some cases, χ3). In addition, the energy was minimized with respect to all of the dihedral angles of the backbone and side chain in the neighborhood of the minima of the contour diagrams, using various minimization procedures, in order to locate the local minima precisely. For poly‐L‐alanine the left‐ and right‐handed α‐helical conformations are those of lowest energy, the right‐handed one being more stable than the left‐handed one by 0.4 kcal/mole. Similar results were obtained for poly‐L‐valine, the right‐handed α helix being more stable than the left‐handed one by 0.5 kcal/mole. In this case, the valyl side chain was found to be rotated around the Cα–Cβ bond by about 10°—15° away from a minimum of the side‐chain torsional‐potential‐energy function. This prediction was verified by recent experiments showing the existence of the α‐helical conformation in a block copolymer of D,L‐lysine, and L‐valine in 98% aqueous methyl alcohol solution. For poly‐β‐methyl‐L‐aspartate, analysis of the energy contributions indicated that, whereas the nonbonded energy would favor the right‐handed form, the interaction of the dipole of the side‐chain ester group with the dipole of the backbone amide group is more repulsive in the right‐handed than in the left‐handed α helix, thereby destabilizing the right‐handed form. In order to demonstrate the importance of this dipole‐dipole interaction, the calculations were repeated for several values of the dielectric constant and of the parameters for the nonbonded interaction potential function. As a result of these calculations, it is suggested that the existence of this polyamino acid in the left‐handed α‐helical form is due to the dipole—dipole interaction between the side chain and the backbone. In contrast, poly‐γ‐methyl‐L‐glutamate was found to have a lower energy in the right‐handed α‐helical form than in the left‐handed one. In this polyamino acid, both the nonbonded and the dipole—dipole interaction energies favor the right‐handed form, i.e., the additional methylene group in the glutamic acid side chain alters the relative orientations of the side‐chain and backbone dipoles so as to lead to a stronger stabilization energy in the right‐handed α helix. Poly‐L‐tyrosine was found to have a lower energy in the right‐handed α‐helical form than in the left‐handed one, the difference in energy between the two forms being 1.8 kcal/mole. The main contribution to the stabilization of the right‐handed form is from the nonbonded energy. In summary, in all the cases examined here, the nonbonded interaction energy would favor the right‐handed α helix over the left‐handed one. However, the dipole—dipole interaction between the side chain and the backbone is apparently of sufficient importance, in the case of the aspartate polymer, to reverse the screw sense.
277 citations