Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual’s genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations

Considerations in Molecular Docking: Presenting DISCO, a DIrectory of Structures for CrossdOcking, as a Novel Docking Benchmark and Applying it to Refine the Molecular Docking Pipeline

Over the past decades, vast improvements have been made in molecular docking techniques and its utilization in binding mode predictions, energy minimization, and lead optimization in drug discovery has become increasingly accepted. Despite this, there are serious shortcomings in the field when it comes to standard methods for measuring docking success and the availability of widely accepted standard datasets for use as a benchmark in comparing different docking algorithms throughout the field. Addressing these issues, we have created DISCO, a DIrectory of Structures for CrossdOcking. DISCO is a versatile crossdocking dataset containing 4,399 protein-ligand complexes across 95 protein targets intended to serve as the go to when it comes to benchmarking pose prediction in molecular docking. DISCO along with a customizable crossdocking dataset generation tool are available at http://www.cs.uofs.edu/~wierbowskis2. We further demonstrate the potential uses of DISCO in questions outside of basic benchmarking, including the application of docked poses produced from DISCO for scoring function optimization and the selection of the ideal docking reference structure

A massively parallel barcoded sequencing pipeline enables generation of the first ORFeome and interactome map for rice

Systematic mappings of protein interactome networks have provided invaluable functional information for numerous model organisms. Here we develop PCR-mediated Linkage of barcoded Adapters To nucleic acid Elements for sequencing (PLATE-seq) that serves as a general tool to rapidly sequence thousands of DNA elements. We validate its utility by generating the ORFeome for Oryza sativa covering 2,300 genes and constructing a high-quality protein-protein interactome map consisting of 322 interactions between 289 proteins, expanding the known interactions in rice by roughly 50%. Our work paves the way for high-throughput profiling of protein-protein interactions in a wide range of organisms