title: The utility of side-chain cyclization in determining the receptor-bound conformation of peptides: cyclic tripeptides and angiotensin II.
abstract: The effect of side-chain cyclization on accessible backbone conformations of tripeptides, X-Ala-Y (X and/or Y = Cys, Hcy (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 phi, psi space were evaluated for each compound, and the ability of the cyclic tripeptides to accommodate beta-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 approximately equal to Hcy-Ala-Cys 4 >> MPc-Ala-Hcy 5, 7 > Cys-Ala-Cys 6 > MPc-Ala-Cys 8 > Hcy-Ala-MPt 9 > Cys-Ala-MPt 10 approximately equal to 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 position 3. 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-Hcy 7 were restricted to a smaller region of phi 2, psi 2 space: the right- and left-handed alpha-helical conformation and the beta-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 phi, psi space: the left-handed alpha-helical conformation for 9-11, plus the beta conformation for 9. This suggests that MP at the 3-position is incompatible with a right-handed alpha-helical conformation at position 2.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Center for Molecular Design, Washington University, St. Louis, Missouri 63130-4899.
authors.forename: T
authors.initials: T
authors.lastname: Kataoka
authors.forename: D D
authors.initials: DD
authors.lastname: Beusen
authors.forename: J D
authors.initials: JD
authors.lastname: Clark
authors.forename: M
authors.initials: M
authors.lastname: Yodo
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000187:drug effects; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011945:Receptors, Angiotensin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D010455:Peptides; D010456:Peptides, Cyclic; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D011957:Receptors, Opioid; D000804:Angiotensin II