Functional Annotation from Structural Homology

Abstract

With the nexus of super computing and the biotech revolution, it seems an era of predictive biology through systems biology may be at hand. Modern omics capabilities enable examination of the state of biological system in exquisite detail. The genome, transcriptome, proteome, and metabolome may all be largely knowable, at least for some model systems, providing a basis for modeling and simulation of molecular mechanisms, or pathways, that could capture a biological system’s emergent properties. However, there are significant challenges remaining that impede the realization of this vision, perhaps the most significant being the missing functional annotation of genes and gene products. For even the most well-studied organisms as much as a third of called genes for a given genome are not annotated and more than half may be tenuous. Homology inferred from sequence similarity is the basis for much of genome annotation. Homology inferred from structural similarity could be a powerful complement to sequence-based annotation methods. Structural biology or structural informatics can be used to assign molecular function and may have increasing utility with the rapid growth of gene sequence databases and emerging methods for structure determination, like structure prediction based on coevolution. Here we describe tools and provide example cases using structural similarity at the level of quaternary structure, domain content, domain topology, and small 3D motifs to infer homology and posit function. Ultimately annotation by similarity, be it 3D structure homology or more classically primary sequence homology, must be founded by accurate annotation of one ortholog in the group—understanding every function encoded by a genome remains a major challenge to life science.