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The coiled coil is a common protein tertiary structure intimately involved in mediating protein recognition and function. Due to their structural simplicity, coiled coils have served as attractive scaffolds for the development of functional biomaterials. Herein we describe the design of conformationally-defined coiled coil photoswitches as potential environmentally-sensitive biomaterials. [ABSTRACT FROM AUTHOR]

Protein–protein interactions (PPIs) are emerging as attractive targets for drug design because of their central role in directing normal and aberrant cellular functions. These interactions were once considered “undruggable” because their large and dynamic interfaces make small molecule inhibitor design challenging. However, landmark advances in computational analysis, fragment screening and molecular design have enabled development of a host of promising strategies to address the fundamental molecular recognition challenge. An attractive approach for targeting PPIs involves mimicry of protein domains that are critical for complex formation. This approach recognizes that protein subdomains or protein secondary structures are often present at interfaces and serve as organized scaffolds for the presentation of side chain groups that engage the partner protein(s). Design of protein domain mimetics is in principle rather straightforward but is enabled by a host of computational strategies that provide predictions of important residues that should be mimicked. Herein we describe a workflow proceeding from interaction network analysis, to modeling a complex structure, to identifying a high-affinity sub-structure, to developing interaction inhibitors. We apply the design procedure to peptidomimetic inhibitors of Ras-mediated signaling. [ABSTRACT FROM AUTHOR]

Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations. Here, we present expansions to the ROSETTA platform that enable structure prediction and design of five non-peptidic oligomer scaffolds (noncanonical backbones), oligooxopiperazines, oligo-peptoids, -peptides, hydrogen bond surrogate helices and oligosaccharides. This work is complementary to prior additions to model noncanonical protein side chains in ROSETTA. The main purpose of our manuscript is to give a detailed description to current and future developers of how each of these noncanonical backbones was implemented. Furthermore, we provide a general outline for implementation of new backbone types not discussed here. To illustrate the utility of this approach, we describe the first tests of the ROSETTA molecular mechanics energy function in the context of oligooxopiperazines, using quantum mechanical calculations as comparison points, scanning through backbone and side chain torsion angles for a model peptidomimetic. Finally, as an example of a novel design application, we describe the automated design of an oligooxopiperazine that inhibits the p53-MDM2 protein-protein interaction. For the general biological and bioengineering community, several noncanonical backbones have been incorporated into web applications that allow users to freely and rapidly test the presented protocols (http://rosie.rosettacommons.org). This work helps address the peptidomimetic community's need for an automated and expandable modeling tool for noncanonical backbones. [ABSTRACT FROM AUTHOR]

Protein secondary and tertiary structure mimics have served as model systems to probe biophysical parameters that guide protein folding and as attractive reagents to modulate protein interactions. Here, we review contemporary methods to reproduce loop, helix, sheet, and coiled‐coil conformations in short peptides. [ABSTRACT FROM AUTHOR]

Summary: HippDB catalogs every protein–protein interaction whose structure is available in the Protein Data Bank and which exhibits one or more helices at the interface. The Web site accepts queries on variables such as helix length and sequence, and it provides computational alanine scanning and change in solvent-accessible surface area values for every interfacial residue. HippDB is intended to serve as a starting point for structure-based small molecule and peptidomimetic drug development.Availability and implementation: HippDB is freely available on the web at http://www.nyu.edu/projects/arora/hippdb. The Web site is implemented in PHP, MySQL and Apache. Source code freely available for download at http://code.google.com/p/helidb, implemented in Perl and supported on Linux.Contact: arora@nyu.edu [ABSTRACT FROM AUTHOR]

Examination of complexes of proteins with other biomolecules reveals that proteins tend to interact with partners via folded subdomains, in which the backbone possesses secondary structure. α-Helices, the largest class of protein secondary structures, play fundamental roles in a multitude of highly specific protein–protein and protein–nucleic acids interactions. Herein, we describe the potential of a helix nucleation strategy to afford modulators of protein–protein interactions. [Copyright &y& Elsevier]

Coiled coils are a major motif in proteins and orchestrate multimerization of various complexes important for biological processes. Inhibition of coiled coil-mediated interactions has significant biomedical potential. However, general approaches that afford short peptides with defined coiled coil conformation remain elusive. We evaluated several strategies to stabilize minimal helical bundles, with the dimer motif as the initial focus. A stable dimeric scaffold was realized in a synthetic sequence by replacing an interhelical ionic bond with a covalent bond. Application of this strategy to a more challenging native protein-protein interaction (PPI) suggested that an additional constraint, a disulfide bond at the internal a/d' position along with a linker at the e/e' position, is required for enhanced conformational stability. We anticipate the coiled coil stabilization methodology described herein to yield new classes of modulators for PPIs. [ABSTRACT FROM AUTHOR]

The modulation of protein-protein interactions (PPIs) by means of creating or stabilizing secondary structure conformations is a rapidly growing area of research. Recent success in the inhibition of difficult PPIs by secondary structure mimetics also points to potential limitations, because often, specific cases require tertiary structure mimetics. To streamline protein structure-based inhibitor design, we have previously described the examination of protein complexes in the Protein Data Bank where α-helices or β-strands form critical contacts. Here, we examined coiled coils and helix bundles that mediate complex formation to create a platform for the discovery of potential tertiary structure mimetics. Though there has been extensive analysis of coiled coil motifs, the interactions between pre-formed coiled coils and globular proteins have not been systematically analyzed. This article identifies critical features of these helical interfaces with respect to coiled coil and other helical PPIs. We expect the analysis to prove useful for the rational design of modulators of this fundamental class of protein assemblies. [ABSTRACT FROM AUTHOR]