The utility of side-chain cyclization in determining the receptor-bound conformation of peptides: cyclic tripeptides and angiotensin II.
The utility of side-chain cyclization in determining the receptor-bound conformation of peptides: cyclic tripeptides and angiotensin II.
复制标题
侧链环化在确定肽的受体结合构象中的应用：环三肽和血管紧张素 II。
DOI：
10.1002/bip.360321110
复制
发表时间：
1992
期刊：
影响因子：
2.9
通讯作者：
Marshall,GR
中科院分区：
文献类型：
--
作者：
Kataoka,T;Beusen,DD;Clark,JD;Yodo,M;Marshall,GR
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), andtrans4‐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‐Ala1≫ Hcy‐Ala‐Hcy2≫ Cys‐Ala‐Hcy3≅ Hcy‐Ala‐Cys4≫ MPc‐Ala‐Hcy5,7> Cys‐Ala‐Cys6> MPc‐Ala‐Cys8> Hcy‐Ala‐MI't9> Cys‐Ala‐MPt10≅ MPc‐Ala‐MPt11. Although Hcy‐Ala‐Hcy2had the greatest number of conformations of the cyclic peptides studied, it was still greatly constrained relative to its linear analogue1. 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 thecisisomer (MPc) at position 1 and/or thetrans isomer(MPt) at position3. Sterically allowed conformations of Ala2for the cyclic tripeptides2‐4were generally similar to those of the linear tripeptide1, while those of Cys‐Ala‐Cys6and MPc‐Ala‐Hey7were restricted to a smaller region of ϕ2, Ψ2space: the right‐ and left‐handed α‐helical conformation and the β‐conformation. This trend was even more pronounced for Hcy‐Ala‐MPt9, Cys‐Ala‐MPt10, and MPc‐Ala‐MPt11, in which Ala2was severely restricted to a very small region of ϕ, Ψ space: the left‐handed α‐helical conformation for9–11, plus the β‐conformation for9. 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 of2and6revealed 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 on2and6were 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. Positionsi+ 1 andi+ 2 of β‐turns were aligned with residues 1 and 2 of theN‐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‐Cys16was 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 …
