Evolution of Protein Structure Degradation and Lessons for the Drug Designer

Abstract

Proteins with common ancestry (homologs) typically share a common fold. This structural similarity introduces major problems for drug design since a therapeutic imperative in drug treatment is the control of specificity. As shown in this chapter, while the folding topology of the native structure is highly similar across homologs, the wrapping and expression regulation patterns tend to be different, offering an opportunity to funnel the impact of a drug solely on clinically relevant targets. The evolutionary root of the subtle dissimilarities across homologous proteins is dissected in this chapter both across species and within the human species. As anticipated in this chapter, the wrapping variations across homologs have profound consequences for drug design as we aim at engineering target-specific and species-specific therapeutic agents and build insightful animal models for disease and malignancy. In assessing the evolutionary forces that promote differences in the dehydron patterns across orthologous proteins (homologs from different species), we came across the surprising finding that random genetic drift plays a central role in causing dehydron enrichment. This type of structural degradation promotes higher protein interactivity and is more pronounced in species with low population, such as humans, where mildly deleterious mutations resulting from random drift have a higher probability of getting fixed in the population. The fitness consequences of nature’s evolutionary strategy are assessed for humans, and reveal the high exposure of the human species to fitness catastrophes resulting from aberrant protein aggregation.