Interactions between proteins are ubiquitous in biology and have recently garnered much attention from the drug discovery and protein engineering community. Although evidence suggests about 80% of proteins exists in one or more protein complexes during their lifetimes, relatively little is known about the structural evolution of protein interfaces and how they can be exploited as drug targets, especially against viruses that mimic human protein interactions. Computational methods for detecting and comparing protein interfaces have gained traction in the past 5 years; however until now they have been limited by the availability of high resolution structures and biased by sequence similarity. We have developed a new algorithm, PC-align, that is capable of detecting subtle geometric similarities in protein interfaces across the PDB and other libraries that can be exploited to predict convergently evolved interfaces that serve as powerful viral drug targets.
Interface Comparison for Development of New Antiviral Biologics
PC-Align overcomes biases caused by global protein sequence and structure to quantitatively compare protein interfaces between seemingly unrelated proteins. Our algorithm utilizes a novel combination of search and comparison algorithms that consider both spatial and chemical similarity to produce “scored” matches based on both the structural and chemical likeness of the two interfaces. In our first implementations of the program, we successfully identified a number of targets that could serve as biological surrogates for viral inhibitors or potential epitopes for vaccine development. This technology embodies a new tool for comparison of protein interfaces, and more importantly, is part of a process for rapid development of viral inhibitors and vaccines.
- Sensitive and Quantitative Comparative Searches of Protein-Protein Interfaces
- Discovery of Protein-based Viral Inhibitors
- Discovery of Expressible Protein-based Epitopes for Vaccines
- Doesn’t rely on detailed sequence-sequence or structure-structure comparisons
- Streamlines vaccine development