Conformational states and biological activity of cyclic peptides

  • Ovchinnikov Y
  • Ivanov V
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Abstract

1. lNTRODUCTlON There is no dearth of literature on the structural,'d synthetic (both artificial " ' and biological'& ") or func-tiona12.3.'2 aspects of cyclopeptide chemistry. Cyclopep-tides. well known for their biological importance as antibiotics, toxins, hormones, ion transport regulators, etc. are the objects of intensive research and thus always in need of periodic stock taking, which is one of the justifications for this review. Yet another and, perhaps, even more important reason is the very strong depen-dence of the physico-chemical and biological properties of these compounds on the spatial arrangement of their constituent atoms and whereas it is this aspect, namely the structure-function relation, which has received either only cursory consideration, " .'3 or has been confined to a very limited number of objects. " The authors have thus set themselves the task of a more comprehensive treatment of the structure-function relation of cyclic peptides and have at the same time included available data on new members of this class, even though they may as yet have been investigated only to a limited degree. One of the difficulties in the approach to the cyclopep-tide conformation (the knowledge of which is an obvious prerequisite to the understanding of their behaviour in oitro and in uiuo and to the prediction on the properties of new representatives) is that, in spite of being more rigid than their linear counterparts, they still possess flexibility to the extent that their spatial structures are environment-dependent, such that in solution they exist as a complex equilibrium of interconverting forms. This necessitates the study of their three-dimensional structure (as of peptides in general) under the most varied conditions and in both solution and the crystanine state. Only by this means can one expect to obtain the key to the why's and wherefore's of their biological function. It is this which defines the scope and limitations of the present review, in which we consider present day methods for describing peptide conformation and also the techniques used in their study. 2. CONFORMATIONAL NOMENCLATURE OF PEPTtDES The spatial structures of peptides may, obviously, be represented by the three-dimensional coordinates of their constituent atoms. This provides a precise description without recourse to any additiofial assumptions. At the the same time the regular structure of the peptide chain +Deviations of amide groups from planarity, although not large, were recently proved to he of a general nature.= " SThe " peptide unit " is C'-C'-N-C* : the " amino acid residue " 8A is that in the chemical sense: -NH-@HR-C'O-and certain stereochemical properties of the amino acid residues and the amide groups provide a simpler and more convenient way of describing such structures, namely by the angles about the bonds of the peptide chain. In the early fifties, from analysis of available X-ray data, Pauling and CoreyI arrived at the conclusion, that the amide bonds of peptides have a planar cis-or trans-configuration, and that bond angles and bond lengths in the backbone depend very little on its size or on the nature of the side chains. The parameters of the truns-amide bond were reported by Pauling and Corey in 1953 and those of the much less frequent cis-amide bond by Ramachandran and Venkatachalam16 in 196% Subsequent investigations " . " have confirmed Pauling and Corey's conclusions, which served as the starting point for the rational conformational nomenclature of peptides.+ " Since in agreement with Pauling and Corey, bond angles and bond lengths in a " peptide unit " + are equal for all peptides, the conformation of a peptide backbone requires for its definition only three independent parame-ters: viz., the rotation angles 4, + and w around the N-C- " . C " -C'-and Cl-N-bonds, respectively. As zero points (4 = $ = w = 0') for the angles, the angles of the fully extended form with the amide bond tram-and the Co-C' and Co-N bonds cis-to the N-H and C-0 bonds (Fig. la) have been adopted. The rotations are measured in the clock-wise direction when looking from the N-to the C-terminus of the respective bond in the backbone. Similar designations were assumed for depsipeptides (Fig. lb). In 1970 the I.U.P.A.C. commission proposed a new nomenclature** and it is this which is used in the present review. The latter differs from the former by a I80 rotation of the 0 " point of all three angles I#B. $ and w and by the angles being measured either clockwise (positive values from 0 " to ISO ") or counter clockwise (negative values from 0 " to 180 "). The new rotation angles are related to the old ones as follows: (4. I). o)~_ = (4, (I, O) " M -180 " . a b

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Authors

  • Yu A. Ovchinnikov

  • V. T. Ivanov

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