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Foldamers: a Manifesto Such Efforts Are Varied, but These Studies Suggest a Collective, Emerging Realization That Control Over Oligomer SAMUEL H

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Foldamers: a Manifesto Such Efforts Are Varied, but These Studies Suggest a Collective, Emerging Realization That Control Over Oligomer SAMUEL H Acc. Chem. Res. 1998, 31, 173-180 ing conformational propensities. The motivations behind Foldamers: A Manifesto such efforts are varied, but these studies suggest a collective, emerging realization that control over oligomer SAMUEL H. GELLMAN* and polymer folding could lead to new types of molecules Department of Chemistry, University of Wisconsin, with useful properties. The purpose of this ªmanifestoº Madison, Wisconsin 53706 is to introduce a large audience to the broad research Received October 6, 1997 horizons offered by the concept of synthetic foldamers. The path to creating useful foldamers involves several daunting steps. (i) One must identify new polymeric backbones with suitable folding propensities. This goal Introduction includes developing a predictively useful understanding Nature relies on large molecules to carry out sophisticated of the relationship between the repetitive features of chemical operations, such as catalysis, tight and specific monomer structure and conformational properties at the binding, directed flow of electrons, or controlled crystal- polymer level. (ii) One must endow the resulting foldam- lization of inorganic phases. The polymers entrusted with ers with interesting chemical functions, by design, by these crucial tasks, mostly proteins but sometimes RNA, randomization and screening (ªevolutionº), or by some are unique relative to other biological and synthetic combination of these two approaches. (iii) For techno- polymers in that they adopt specific compact conforma- logical utility, one must be able to produce a foldamer tions that are thermodynamically and kinetically stable. efficiently, which will generally include preparation of the These folding patterns generate ªactive sitesº via precise constituent monomers in stereochemically pure form and three-dimensional arrangement of functional groups. In optimization of heteropolymer synthesis. Each of these terms of covalent connectivity, the groups that comprise steps involves fascinating chemical challenges; the first the active site are often widely spaced along the polymer step is the focus of this Account. backbone. The remarkable range of chemical capabilities that Principles evolution has elicited from proteins suggests that it might As one sets out to create synthetic foldamers, it is useful be possible to design analogous capabilities into unnatural to identify general principles that govern the conforma- polymers that fold into compact and specific conforma- tions of the biofoldamers, proteins and RNA. Three tions. Since biological evolution has operated under many principles seem to be particularly important: (i) hierarchi- constraints, the functional properties of proteins and RNA cal organization of conformation (secondary structure vs should be viewed as merely exemplifying the potential of tertiary structure); (ii) cooperativity in higher order struc- compactly folded polymers. The chemist's domain in- tures; (iii) sequence heterogeneity. These three principles cludes all possible combinations of the elements, and the are elaborated upon below. biological realm, vast and complex though it may be, is Conformational analysis of both proteins1 and RNA2 is only a small part of that domain. Therefore, realization hierarchical. For proteins, the term ªsecondary structureº of the potential of folding polymers may be limited more refers to local conformational preferences of the poly(R- by the human imagination than by physical barriers. amino acid) backbone. The most common regular ele- I use the term ªfoldamerº to describe any polymer with ments of secondary structure include R-helices, â-turns, a strong tendency to adopt a specific compact conforma- and â-strands; â-strands are usually found in side-by-side tion. Among proteins, the term ªcompactº is associated sets that comprise â-sheets. The ªtertiary structureº of a with tertiary structure, and there is as yet no synthetic protein is the way in which various elements of regular polymer that displays a specific tertiary structure. Protein secondary structure, and irregular connecting segments, tertiary structure arises from the assembly of elements of are packed together. For RNA, secondary structure refers regular secondary structure (helices, sheets, and turns). to the pattern of base pair formation, and tertiary structure The first step in foldamer design must therefore be to is the three-dimensional packing of duplex and nonduplex identify new backbones with well-defined secondary segments. Thus, the concepts of tertiary structure are structural preferences. ªWell-definedº in this case means comparable for the two biofoldamers, but the concepts that the conformational preference should be displayed of secondary structure differ, which reflects a key differ- in solution by oligomers of modest length, and I will ence in the network of noncovalent forces that specifies designate as a foldamer any oligomer that meets this folding in proteins and RNA. In proteins, regular second- criterion. Within the past decade, a handful of research ary structures are defined largely in terms of H-bonding groups have described unnatural oligomers with interest- between sites embedded in the polymeric backbone, while in RNA, regular secondary structure is defined in terms Samuel H. Gellman earned an A.B. in chemistry from Harvard University in 1981 of base pairing. It should be noted that these defining and a Ph.D. from Columbia University in 1986. In 1987, after 18 months of interactions are not necessarily the only, or even the postdoctoral research at the California Institute of Technology, Gellman moved to the University of WisconsinsMadison, where he is currently a Professor of major, driving forces for observed secondary structures; Chemistry. * E-mail: [email protected]. S0001-4842(96)00298-1 CCC: $15.00 1998 American Chemical Society VOL. 31, NO. 4, 1998 / ACCOUNTS OF CHEMICAL RESEARCH 173 Published on Web 03/13/1998 Foldamers Gellman other important factors include the intrinsic conforma- tional preferences of the backbone, dispersion interac- tions, polar interactions, and solvation (e.g., the hydro- phobic effect). The sophisticated chemical functions carried out by the biofoldamers nearly always require a specific tertiary fold, presumably because it is only at the level of tertiary structure that there is enough structural variation to allow FIGURE 1. Poly(R-amino acid) backbone. The solid curved arrows wide latitude in the arrangement of the functional groups indicate H-bonds associated with the two types of helices in proteins. that constitute the active site. Proteins and RNA seem to The dotted curved arrows indicate ªnearest-neighborº H-bonds, teach us, however, that we will not be able to generate which are unfavorable. new tertiary structures until we know how to identify of foldamer development, however, since heterogeneity unnatural backbones that are predisposed to adopt spe- is not necessary to explore the possibility of long-range cific secondary structures. The types of secondary struc- secondary structural order in a given backbone. ture most crucial for foldamer development are those that display long-range order, helices and sheets. Chan and Dill have predicted that these two long-range secondary â-Peptides: A Case Study structures will be characteristic of all compactly folded Within the past decade, the folding properties of several 3 polymers. Strictly local secondary structures, like â-turns types of synthetic oligomers with unnatural backbones and other loops, should be relatively easy to contrive once have been explored. I will focus on oligo(â-amino acids) a backbone with suitable long-range folding properties is (ªâ-peptidesº), because this type of oligomer is among the identified. most thoroughly characterized at present, in terms of Cooperativity is probably essential to sophisticated folding properties. Seebach's group at the ETH in ZuÈrich5 chemical functions, since this feature guarantees the and our group6 have been the most active in the explora- integrity of active sites in the folded state. Active sites tion of short â-peptides.7 are generally comprised of functional groups drawn from Our initial efforts were aimed at identifying backbones different regions of the linear polypeptide chain. A that favored helical secondary structures. Devising mini- cooperatively folded structure will have all the important mum increments of helix is simpler than devising mini- groups in place at the same time, since the entire structure mum increments of sheet, since creating a sheet incre- is more stable than the sum of its parts. A single long ment requires that one identify a nonsheet segment with segment of R-helix, for example, is more stable than which to link adjacent strands. This topological distinc- several short R-helical segments, of equivalent total tion underlies a remarkable dichotomy in protein sci- length.4 Protein tertiary structure formation is also ence: there is considerable information on the properties cooperative: partially folded states are less stable than of isolated helices,8 but little information on the properties either the native state or the denatured state.1 Therefore, of isolated sheets, because soluble helix models are readily proteins tend not to unravel a little bit at a time, but available, while soluble sheet models are hard to come rather, when sufficiently mistreated, to come apart all at by. once. This behavior means that a protein's tertiary We suspected that two features of protein helices (R 6a structure
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