Year: 2017
Type: editorial
Abstract: Cells execute their functions through protein interactions.The pathways they link are neither discrete nor spatially separated, as typically depicted in cellular diagrams.Cellular diagrams are useful; however, they neglect the physical structure of cell signaling.In reality, functions are shaped by molecular transitions between small-and large-supramolecular assemblies.Even though they are preorganized, they consist of clusters that are loose and dynamic.Importantly too, they are often anchored in the membrane and interact with scaffolding proteins and the cytoskeleton.Their continuum may physically span the cell.Indeed, efficient, productive, and reliable cell signaling can only take place through transient and cooperative protein-protein interactions, not through stochastic, diffusion-controlled processes.Despite this, current computational approaches to the modeling of the structural proteome still do not fully account for the in vivo, real physical cell organization.The enigmas of the assembly sizes and dynamic conformational distributions-and the diverse cellular environments that influence thempresent daunting challenges, which we have only begun to address.How will we then compute the realistic structural proteome in the next decade?How will we overcome the challenges that we confront, and which methods should we develop to meet them?Clearly, our views of protein structure and function have undergone a revolution.We no longer believe that a protein exists in only two distinct (active and inactive) states.We now recognize that even though a specific function is executed by a distinct active state, proteins (and other bio-macromolecules) exist in ensembles of states.The structure-function paradigm that now dominates molecular biology was inspired by physics and chemistry, which stipulate that even living things must abide by the laws of quantum mechanics and structural chemistry.This paradigm argues that biomolecules should be viewed-and described-statistically, not statically.Though challenging, eventually, to realistically capture the functional versatility and model the working proteome, we must consider conformational ensembles and their allosteric shifts, which result in changes to the populations of the conformations.Moreover, within this framework, the heterogeneous cellular environments, as well as allosteric covalent post-translational modifications, cannot be overlooked.Have we indeed treated the structural proteome as such in our computations?Determining the structures of protein assemblies has long been a vastly important aim of structural biology.The problem is challenging: a pair of protein structures can interact by complementary patches of surfaces.The patch size and identity are unknown, and it is difficult to assess which patches on one protein interact with which patches on the other.In principle,
Source: PLoS Computational Biology
Authors: Ruth Nussinov, Jason A. Papin, Ilya Vakser
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
OpenAlex ID: W2577454214