Dataset Information

Design criteria for minimalist mimics of protein-protein interface segments.

ABSTRACT: Small molecules that can interrupt or inhibit protein-protein interactions (PPIs) are valuable as probes in chemical biology and medicinal chemistry, but they are also notoriously difficult to develop. Design of non-peptidic small molecules that mimic amino acid side-chain interactions in PPIs ("minimalist mimics") is seen as a way to fast track discovery of PPI inhibitors. However, there has been little comment on general design criteria for minimalist mimics, even though such guidelines could steer construction of libraries to screen against multiple PPI targets. We hypothesized insight into general design criteria for minimalist mimics could be gained by comparing preferred conformations of typical minimalist mimic designs against side-chain orientations on a huge number of PPI interfaces. That thought led to this work which features nine minimalist mimic designs: one from the literature, and eight new "hypothetical" ones conceived by us. Simulated preferred conformers of these were systematically aligned with >240?000 PPI interfaces from the Protein Data Bank. Conclusions from those analyses did indeed reveal various design considerations that are discussed here. Surprisingly, this study also showed one of the minimalist mimic designs aligned on PPI interface segments more than 15 times more frequently than any other in the series (according to uniform standards described herein); reasons for this are also discussed.

SUBMITTER: Taechalertpaisarn J

PROVIDER: S-EPMC6344279 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design criteria for minimalist mimics of protein-protein interface segments.

Taechalertpaisarn Jaru J Lyu Rui-Liang RL Arancillo Maritess M Lin Chen-Ming CM Jiang Zhengyang Z Perez Lisa M LM Ioerger Thomas R TR Burgess Kevin K

Organic & biomolecular chemistry 20190101 4

Small molecules that can interrupt or inhibit protein-protein interactions (PPIs) are valuable as probes in chemical biology and medicinal chemistry, but they are also notoriously difficult to develop. Design of non-peptidic small molecules that mimic amino acid side-chain interactions in PPIs ("minimalist mimics") is seen as a way to fast track discovery of PPI inhibitors. However, there has been little comment on general design criteria for minimalist mimics, even though such guidelines could ...[more]

PMID: 30629068

Similar Datasets

Project description:Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, "minimalist helical mimics". It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i + 4, i + 7 side-chains in orientations that best resemble an ideal ?-helix, and is a different mimic required for a i, i + 3, i + 7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of C? and C? coordinates corresponding to three amino acid side-chains displayed by the scaffolds; (iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of C? and C? coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay C? and C? coordinates of all the conformers on all the sets of side-chain "triads" in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the "side-chain correspondences" (e.g. i, i + 4, i + 7 or i, i + 3, i + 4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist ?-helical mimics (1-8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as ?-helices, and many of the ?-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein-protein interaction sites.

Project description:BACKGROUND: Microarray comparative genomic hybridization (CGH) is currently one of the most powerful techniques to measure DNA copy number in large genomes. In humans, microarray CGH is widely used to assess copy number variants in healthy individuals and copy number aberrations associated with various diseases, syndromes and disease susceptibility. In model organisms such as Caenorhabditis elegans (C. elegans) the technique has been applied to detect mutations, primarily deletions, in strains of interest. Although various constraints on oligonucleotide properties have been suggested to minimize non-specific hybridization and improve the data quality, there have been few experimental validations for CGH experiments. For genomic regions where strict design filters would limit the coverage it would also be useful to quantify the expected loss in data quality associated with relaxed design criteria. RESULTS: We have quantified the effects of filtering various oligonucleotide properties by measuring the resolving power for detecting deletions in the human and C. elegans genomes using NimbleGen microarrays. Approximately twice as many oligonucleotides are typically required to be affected by a deletion in human DNA samples in order to achieve the same statistical confidence as one would observe for a deletion in C. elegans. Surprisingly, the ability to detect deletions strongly depends on the oligonucleotide 15-mer count, which is defined as the sum of the genomic frequency of all the constituent 15-mers within the oligonucleotide. A similarity level above 80% to non-target sequences over the length of the probe produces significant cross-hybridization. We recommend the use of a fairly large melting temperature window of up to 10 C, the elimination of repeat sequences, the elimination of homopolymers longer than 5 nucleotides, and a threshold of -1 kcal/mol on the oligonucleotide self-folding energy. We observed very little difference in data quality when varying the oligonucleotide length between 50 and 70, and even when using an isothermal design strategy. CONCLUSIONS: We have determined experimentally the effects of varying several key oligonucleotide microarray design criteria for detection of deletions in C. elegans and humans with NimbleGen's CGH technology. Our oligonucleotide design recommendations should be applicable for CGH analysis in most species.

Dataset Information

Design criteria for minimalist mimics of protein-protein interface segments.

Publications

Design criteria for minimalist mimics of protein-protein interface segments.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets