Folding of Polypeptide Chains in Proteins: A Proposed Mechanism for Folding

Lewis, Peter N.; Momany, Frank A.; Scheraga, Harold A.

doi:10.1073/pnas.68.9.2293

Cited by 305 publications

(142 citation statements)

References 7 publications

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“…This conformational stability illustrates the importance of local interactions between near-neighbor peptide units to peptide conformation, suggesting that certain peptide sequences may have an intrinsic tendency to adopt a 310-bend conformation. Lewis, Momany & Scheraga (1971) have pointed out that such sequences in proteins would have an important directing effect on the folding of the polypeptide chain. They have devised an empirically-based scheme for predicting the occurrence of bends in proteins.…”

Section: Discussionmentioning

confidence: 99%

The crystal structure of S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide and its selenium analog

Rudko¹,

Low²

1975

Acta Crystallogr Sect B

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The crystal structure of the protected C-terminal tetrapeptide fragment of oxytocin, S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide, has been determined, as well as that of the analogous peptide in which sulfur is replaced by selenium. The crystals of both compounds are monoclinic, space group P21. Lattice constants are a= 13.65, b=8.97, c=20.27 A,, fl=93.33 ° for the sulfur peptide and a= 13.71, b = 9.07, c= 20.31A., fl= 94-00 ° for the nearly isomorphous selenium peptide. The selenium analog structure was solved by the heavy-atom method. The atomic parameters so derived were used as a starting point for the refinement of both structures. The least-squares refinement was not straightforward; the selenium peptide would refine to an R value of only 0.21, while the sulfur peptide was finally refined to an R value of 0.085. There are two molecules in the asymmetric unit with very similar conformations and orientations, related by a translation of approximately ¼b+½c. The peptides are in a compact '3L0 bend' conformation with an intramolecular hydrogen bond between the carbonyl oxygen of the cysteinyl residue and the amide nitrogen of the leucyl residue. In one of the molecules in the asymmetric unit there is a second hydrogen bond between the carbonyl oxygen of the prolyl residue and the C-terminal amide nitrogen.

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Section: Discussionmentioning

confidence: 99%

The crystal structure of S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide and its selenium analog

Rudko¹,

Low²

1975

Acta Crystallogr Sect B

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“…We have associated joint fragments with turns (7) that tend to appear on the surface of proteins and to contain a high percentage of glycines. Thus, it seems most reasonable to assume that they constitute extremely flexible chain segments and that they play a passive (8) rather than directing role (9) A second type of calculation performed was the minimization of the interaction energy of two rigid regions with respect to the protational angles in the chain fragment that separates them. The conformation obtained is compared to the crystal structure through the root mean square (rms) deviation of the energy-minimized coordinates from the crystal coordinates.…”

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confidence: 99%

Conformational flexibility and protein folding: rigid structural fragments connected by flexible joints in subtilisin BPN.

Ray¹,

Levinthal²

1976

Proc. Natl. Acad. Sci. U.S.A.

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Conformational energy calculations are used to analyze the interactions of structural substructures in subtilisin BPN. These substructures are kept fixed or-"rigid" so that the only variables in the calculations are the backbone segments that separate them. The flexible segments are assumed to be free turns. Using this representation of the protein it is possible to predict both a likely order of events along a folding pathway and preferred modes of conformational changes of the native protein. Moreover, when the native structure has been perturbed by moving the substructures apart, it is possible to assess the range of interactions that return the protein, upon energy minimization, to its original conformation. These results suggest an approach to the folding problem based on the piecemeal formation of tertiary structure from smaller prefolded fragments.The information necessary to determine the three-dimensional structure of a folded protein is contained in its sequence of amino acids (1). Thus, it should be possible in principle to predict the geometry of a protein from its primary structure. However, it does not seem possible that the final conformation of a protein is established by selecting the lowest energy state from among all possible conformations. The time required for random motion to produce all possible states would be many orders of magnitude longer than the observed folding time (2). In addition, a search of all possible states would presumably result in the structure's being trapped in some "incorrect" local minimum (unless biological evolution specifically selected against this possibility). Thus, an elucidation of the folding pathway is an essential step in discovering the relationship between the primary and tertiary structure of a protein.We assume that proteins fold by following a multiply. branched pathway in which the first stage is the formation of local secondary structure governed by interactions between amino acids that are near each other in the peptide chain. Subsequently, these structures, such as a-helices and antiparallel fl-strands, would interact, perhaps being modified in the process, to produce larger structural fragments which then undergo further assembly to yield the native conformation, which we assume to correspond to the crystal conformation. In fact, there is considerable evidence for the existence of "independent" structural fragments of tertiary structure. For example, Rao and Rossman (3) have noted similar patterns of secondary structure organization in a number of proteins. Wetlaufer (4) has emphasized the existence of large globular domains that have been noticed in many proteins although it has not yet been possible to establish unique criteria for their identification. However, in a number of cases (e.g., immunoglobulins, serine proteases) the proteins are clearly formed of distinct domains.The existence of independent structural regions of various sizes provides an enormous simplification for computational efforts to predict structure from sequence. I...

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“…In C3, this region contains seven charged groups and probably lies on the surface ofthe molecule, whereas in C4 and a2M, single charged residues only are found, suggesting the regions to be at least partially interior. In addition, there is a strong potential for a ,(3turn (47,48) around the proline at position 10 in C4 but no such potential in the coincident regions in C3 and a2M. C4 also has differences to C3 and a2M in the highly conserved region 16-46, notably the inclusion of four basic residues (arginine-18, -21, and -39 and lysine-43).…”

Section: Discussionmentioning

confidence: 99%

Sequence determination of the thiolester site of the fourth component of human complement.

Harrison¹,

Thomas²,

Tack³

1981

Proc. Natl. Acad. Sci. U.S.A.

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Communicated by Elkan R. Blout, August 21, 1981 ABSTRACT The fourth component of complement (C4) is inactivated by treatment with methylamine. This property is shared with the third component (C3) and with a%-macroglobulin. In each instance, the reaction with methylamine is stoichiometric, covalent, and accompanied-by the appearance of-a thiol group. These data are consistent with the presence of an internal thiolester ["'C]methylamide was released at step 24. The recovery of radiolabel at positions 21 and 24 confirmedthe originally calculated "'C/ 3H incorporation ratio and further indicated that the radiolabels were present at single sites in the C4 molecule. Comparison of the derived primary structure for the thiolester site in C4 with those for the corresponding regions in C3 and a2-macroglobulin has shown sequence identity. Further comparisons among these three proteins have indicated additional homologies on both the NH2-and COOH-terminal sides of the thiolester site.In the classical pathway ofcomplement (C) activation, the fourth component, C4, is cleaved by Cls, a subcomponent ofactivated CL, into two fragments, C4a and C4b. The larger ofthese, C4b, has the transient ability to bind to surfaces and functions as a component of the classical pathway C3 convertase, C4b2a. These properties are analogous to those of C3, which, on activation, is split into the two fragments C3a and C3b. C3b also acquires a transient ability to bind to surfaces and functions as a component of the alternative pathway C3 convertase, C3bBb (1-3). The interaction between C3b and cell surface components is now known to be, in part, covalent (4). Studies of the chemical reactivity of this bond suggested that it was an oxygen ester, and that the acyl group donor was contained in C3b. These observations led to the hypothesis that covalent bond formation occurred via a transesterification reaction (5).Both C4 and C3 have long been known to be inactivated by treatment with nitrogen nucleophiles such as ammonia or hydrazine (6-8) and by chaotropic salts such as KCNS (9). Recently, treatment of C3 with the nucleophilic reagent methylamine, or with the chaotrope KBr, was shown to result in the loss ofpotential for covalent bond formation and the appearance of a. single thiol group (10-13). This thiol is also released on activation of C3 to C3b (13). These data, and the observed stoichiometric relationship between uptake of methylamine into a glutamyl residue and titration of a thiol (10), led to the hypothesis that an internal thiolester exists in C3 and that covalent bond formation involves transfer ofthe acyl group from the thiol to a hydroxyl contained on the acceptor molecule (10,11,14). These studies of C3 have now been extended to C4. Treatment with nitrogen nucleophiles such as methylamine again results in the titration of a single reactive group, the release of a thiol (which is also contained in C4b), and the loss of covalent bondforming potential (14-19). Recently, in addition to ester bonds between these molecules and binding ...

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Folding of Polypeptide Chains in Proteins: A Proposed Mechanism for Folding

Cited by 305 publications

References 7 publications

The crystal structure of S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide and its selenium analog

The crystal structure of S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide and its selenium analog

Conformational flexibility and protein folding: rigid structural fragments connected by flexible joints in subtilisin BPN.

Sequence determination of the thiolester site of the fourth component of human complement.

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