Library

Notes: The effect of side-chain cyclization on accessible backbone conformations of tripeptides, X-Ala-Y (X and/or Y = Cys, Hey (Hcy: homocysteine), cis 4-mercaptoproline (MPc), and trans 4-mercaptoproline (MPt)), was elucidated using two variants of systematic conformational search. In addition to cyclization through a disulfide bond, the thioether (-S-CH2-) and amide (-CO-NH-) side-chain analogues of Cys-Ala-Cys and Hcy-Ala-Hcy were evaluated. The number of valid backbone conformations and the allowed φ Ψ;space were evaluated for each compound, and the ability of the cyclic tripeptides to accommodate β-turn conformations was examined in order to assess the value of cyclization in limiting conformational freedom. Based on the number of conformations, cyclization was highly effective in reducing the backbone degree of freedom: in order of decreasing number of conformations, Ala-Ala-Ala 1 ≫ Hcy-Ala-Hcy 2 ≫ Cys-Ala-Hcy 3≅ Hcy-Ala-Cys 4 ≫ MPc-Ala-Hcy 5, 7 〉 Cys-Ala-Cys 6 〉 MPc-Ala-Cys 8 〉 Hcy-Ala-MI't 9 〉 Cys-Ala-MPt 10 ≅ MPc-Ala-MPt 11. Although Hcy-Ala-Hcy 2 had the greatest number of conformations of the cyclic peptides studied, it was still greatly constrained relative to its linear analogue 1. The bicyclic ring system introduced by MP was even more effective in constraining the cycle, having greater impact at position 3 than at position 1. Under the conditions of the study, cyclization of MP-containing analogues could be effected only with the cis isomer (MPc) at position 1 and/or the trans isomer (MPt) at position3. Sterically allowed conformations of Ala2 for the cyclic tripeptides 2-4 were generally similar to those of the linear tripeptide 1, while those of Cys-Ala-Cys 6 and MPc-Ala-Hey 7 were restricted to a smaller region of φ2, Ψ2 space: the right- and left-handed α-helical conformation and the β-conformation. This trend was even more pronounced for Hcy-Ala-MPt 9, Cys-Ala-MPt 10, and MPc-Ala-MPt 11, in which Ala2 was severely restricted to a very small region of φ, Ψ space: the left-handed α-helical conformation for 9-11, plus the β-conformation for 9. This suggests that MP at the 3-position is incompatible with a right-handed α-helical conformation at position 2. A similar analysis of the thioether-bridged analogs of 2 and 6 revealed their number of conformers and accessible φ, Ψ regions to be slightly smaller than those of the parent disulfide-bridged compounds. By the same measures, amide-bridged derivatives based on 2 and 6 were even more restricted. N-membered cyclic peptides having an amide (CH2-CO-NH-CH2) bridge yielded results similar to that of the corresponding (n - 1)-membered cyclic peptide having a disulfide bridge.N-acetyl-cyclotripeptides and cyclotripeptide-N-methylamides were used as a model of the four consecutive residues of β-turns to determine if β-turns. could be accommodated. Positions i + 1 and i + 2 of β-turns were aligned with residues 1 and 2 of the N-acetyl-cyclotripeptides (form A), and with residues 2 and 3 of the cyclotripeptide-N-methylamides (form B). Cyclic tripeptides having MP at residue 3 could not accommodate any type of β-turn, while MP at residue 1 ruled out a form B III' β-turn. Peptides not containing MP could accommodate a form A III' β-turn as well as form B I and III β-turns. The thioether-and amide-bridged peptides yielded results similar to the disulfide-bridged peptides on which they were based, although the amide analogue of Cys-Ala-Cys 16 was consistent with only form A β III' and form B βIII turns. None of the cyclic tripeptides examined could accommodate a form A βI turn. Cyclizations were effective in increasing the probability of inducing the backbone of these peptides to adopt β-turns.These results were used, as an example, in the analysis of structure-activity data of cyclically constrained analogues of angiotensin II. A receptor-bound conformation in which Tyr4 assumes the backbone conformation associated with a left-handed a-helix is consistent with the data in the literature. © 1992 John Wiley & Sons, Inc.

Notes: Energy calculations have been performed on right-handed helical structures of L-alanine and α-methylalanine oligomers. A new ′3.610′-helix is described for α-methylalanine peptides. The dependence of the relative stability of the α, 310, and 3.610 structural forms on helix length, dielectric, and force-field, in the gas phase, has been studied. Potential energy surfaces for the interconversion of helices have been generated. The 310-helix in α-methylalanine oligomers exhibits a degree of enthalpic and entropic stabilization not observed for alanine. The relevance of the results to the formation of voltage-sensitive ion channels is discussed.