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Foldamers with heterogeneous backbones.

ABSTRACT: The functions performed by proteins and nucleic acids provide the foundation for life. Chemists have recently begun to ask whether it is possible to design synthetic oligomers that approach the structural and functional complexities of these biopolymers. The study of foldamers, non-natural oligomers displaying discrete folding propensities, has demonstrated that there are several synthetic backbones that exhibit biopolymer-like conformational behavior. Early work in this area focused on oligomers comprised of a single type of monomer subunit, but recent efforts have highlighted the potential of mixed or "heterogeneous" backbones to expand the structural and functional repertoire of foldamers. In this Account, we illustrate the promise of heterogeneous backbone foldamers by focusing on examples containing both alpha- and beta-amino acid residues. Some beta-residues bear protein-like side chains, while others have cyclic structures that confer conformational rigidity. The study of heterogeneous backbone foldamers has several advantages over that of their homogeneous backbone counterparts, including access to many new molecular shapes based on variations in the stoichiometries and patterns of the subunit combinations and improved prospects for side chain diversification. Recent efforts to develop alpha/beta-peptide foldamers can be divided into two conceptually distinct classes. The first includes entities prepared using a "block" strategy, in which alpha-peptide segments and beta-peptide segments are combined to form a hybrid oligomer. The second class encompasses designs in which alpha- and beta-amino acid monomers are interspersed in a regular pattern throughout an oligomer sequence. One alpha/beta-peptide helical secondary structure, containing C=O(i)...H-N(i+4) H-bonds analogous to those in the alpha-helix, has been shown via crystallography to form helix bundle quaternary structures. Desirable biological functions have been elicited from alpha/beta-peptide foldamers. Efforts to mimic naturally occurring host-defense alpha-peptides have yielded new antimicrobial agents and have led to a reexamination of the long-held views regarding structure-activity relationships among these alpha-peptides and their analogues. Foldamers offer new platforms for mimicry of the molecular surfaces involved in specific protein-protein recognition events; recent achievements in the preparation of alpha/beta-peptide inhibitors of the protein-protein interactions involved in apoptotic signaling (e.g., between Bcl-xL and pro-apoptotic partners) have revealed the benefits of employing heterogeneous backbones relative to homogeneous backbones for foldamer-based designs. These initial successes in the development of alpha/beta-peptides exhibiting specific biological activities highlight the potential of heterogeneous backbone foldamers for use in biomedical applications and provide guidelines for future studies into new target functions.

SUBMITTER: Horne WS

PROVIDER: S-EPMC2689379 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Foldamers with heterogeneous backbones.

Horne W Seth WS Gellman Samuel H SH

Accounts of chemical research 20080701 10

The functions performed by proteins and nucleic acids provide the foundation for life. Chemists have recently begun to ask whether it is possible to design synthetic oligomers that approach the structural and functional complexities of these biopolymers. The study of foldamers, non-natural oligomers displaying discrete folding propensities, has demonstrated that there are several synthetic backbones that exhibit biopolymer-like conformational behavior. Early work in this area focused on oligomer ...[more]

PMID: 18590282

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Project description:Progress has been made in understanding how temporal network features affect the percentage of nodes reached by an information diffusion process. In this work, we explore further: which node pairs are likely to contribute to the actual diffusion of information, i.e., appear in a diffusion trajectory? How is this likelihood related to the local temporal connection features of the node pair? Such deep understanding of the role of node pairs is crucial to tackle challenging optimization problems such as which kind of node pairs or temporal contacts should be stimulated in order to maximize the prevalence of information spreading. We start by using Susceptible-Infected (SI) model, in which an infected (information possessing) node could spread the information to a susceptible node with a given infection probability ? whenever a contact happens between the two nodes, as the information diffusion process. We consider a large number of real-world temporal networks. First, we propose the construction of an information diffusion backbone GB(?) for a SI spreading process with an infection probability ? on a temporal network. The backbone is a weighted network where the weight of each node pair indicates how likely the node pair appears in a diffusion trajectory starting from an arbitrary node. Second, we investigate the relation between the backbones with different infection probabilities on a temporal network. We find that the backbone topology obtained for low and high infection probabilities approach the backbone GB(????0) and GB(??=?1), respectively. The backbone GB(????0) equals the integrated weighted network, where the weight of a node pair counts the total number of contacts in between. Finally, we explore node pairs with what local connection features tend to appear in GB(??=?1), thus actually contribute to the global information diffusion. We discover that a local connection feature among many other features we proposed, could well identify the (high-weight) links in GB(??=?1). This local feature encodes the time that each contact occurs, pointing out the importance of temporal features in determining the role of node pairs in a dynamic process.

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Foldamers with heterogeneous backbones.

Publications

Foldamers with heterogeneous backbones.

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