On protein structure, function and modularity from an evolutionary perspective

Abstract: We are compounded entities, given life by a complex molecular machinery. When studying these molecules we have to make sense of a diverse set of dynamical nanostructures with wast and intricate patterns of interactions. Protein polymers is one of the major groups of building blocks of such nanostructures which fold up into more or less distinct three dimensional structures. Due to their shape, dynamics and chemical properties proteins are able to perform a plethora of specific functions essential to all known cellular lifeforms.The connection between protein sequence, translated into protein structure and in the continuation into protein function is well accepted but poorly understood. Malfunction in the process of protein folding is known to be implicated in natural aging, cancer and degenerative diseases such as Alzheimer's.Protein folds are described hierarchically by structural ontologies such as SCOP, CATH and Pfam all which has yet to succeed in deciphering the natural language of protein function. These paradigmatic views centered on protein structure fail to describe more mutable entities, such as intrinsically disordered proteins (IDPs) which lack a clear defined structure.As of 2012, about two thirds of cancer patients was predicted to survive past 5 years of diagnosis. Despite this, about a third do not survive and numerous of successfully treated patients suffer from secondary conditions due to chemotherapy, surgery and the like. In order to handle cancer more efficiently we have to better understand the underlying molecular mechanisms.Elusive to standard methods of investigation, IDPs have a central role in pathology; dysfunction in IDPs are key factors in cellular system failures such as cancer, as many IDPs are hub regulators for major cell functions. These IDPs carry short conserved functional boxes, that are not described by known ontologies, which suggests the existence of a smaller entity. In an investigation of a pair of such boxes of c-MYC, a plausible structural model of its interacting with Pin1 emerged, but such a model still leaves the observer with a puzzle of understanding the actual function of that interaction.If the protein is represented as a graph and modeled as the interaction patterns instead of as a structural entity, another picture emerges. As a graph, there is a parable from that of the boxes of IDPs, to that of sectors of allosterically connected residues and the theory of foldons and folding units. Such a description is also useful in deciphering the implications of specific mutations.In order to render a functional description feasible for both structured and disordered proteins, there is a need of a model separate from form and structure. Realized as protein primes, patterns of interaction, which has a specific function that can be defined as prime interactions and context. With function defined as interactions, it might be possible that the discussion of proteins and their mechanisms is thereby simplified to the point rendering protein structural determination merely supplementary to understanding protein function.