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Folding Thermodynamics of Protein-Like Oligomers with Heterogeneous Backbones.

ABSTRACT: The thermodynamics of protein folding are dictated by a complex interplay of interatomic interactions and physical forces. A variety of unnatural protein-like oligomers have the capacity to manifest defined folding patterns. While the energetics of folding in natural proteins is well studied, little is known about the forces that govern folding in modified backbones. Here, we explore the thermodynamic consequences of backbone alteration on protein folding, focusing on two types of chemical changes made in different structural contexts of a compact tertiary fold. Our results reveal a surprising favorable impact on folding entropy that accompanies modifications that increase disorder in the ensemble of unfolded states, due to differences in the solvation of natural and unnatural backbones.

SUBMITTER: Reinert ZE

PROVIDER: S-EPMC4111276 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Folding Thermodynamics of Protein-Like Oligomers with Heterogeneous Backbones.

Reinert Zachary E ZE Horne W Seth WS

Chemical science 20140801 8

The thermodynamics of protein folding are dictated by a complex interplay of interatomic interactions and physical forces. A variety of unnatural protein-like oligomers have the capacity to manifest defined folding patterns. While the energetics of folding in natural proteins is well studied, little is known about the forces that govern folding in modified backbones. Here, we explore the thermodynamic consequences of backbone alteration on protein folding, focusing on two types of chemical chang ...[more]

PMID: 25071931

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Project description: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.

Dataset Information

Folding Thermodynamics of Protein-Like Oligomers with Heterogeneous Backbones.

Publications

Folding Thermodynamics of Protein-Like Oligomers with Heterogeneous Backbones.

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