Although the misassembly of protein and nucleoprotein complexes is implicated in many regulatory disorders, we have extremely limited knowledge of the mechanisms by which these complexes assemble in vivo. Because many proteins must associate into higher-order assemblies in order to carry out their biological functions, predicting the self-assembly of these complexes is crucial for understanding the organization and regulation of the proteome. Experimental investigations of the assembly of these complexes are complicated by the fact that many essential complexes, including the ribosome and the proteasome, contain dozens of subunits that assemble in a highly cooperative manner. Furthermore, it is now known that assembly in vivo differs signi?cantly from reconstitution experiments conducted under dilute conditions, particularly due to the presence of molecular chaperones that act as assembly co-factors. New theoretical approaches are thus needed to cope with this complexity and to identify the physical principles governing robust self-assembly and regulation at the proteomic level. Building on a powerful theory of self-assembly that I have recently developed to describe DNA-based nanostructures, I shall establish a novel theoretical approach for predicting the assembly pathways of protein and nucleoprotein complexes. This approach will provide a considerably more complete picture of the mechanism of assembly than can be obtained from experiments alone and is orders of magnitude more ef?cient than conventional simulations. Leveraging this ef?ciency to perform computational screens that were previously intractible, I shall test the hypothesis that nucleoprotein complexes have evolved to optimize the rate of assembly. I shall also investigate the sensitivity of self-assembly to variations in subunit stoichiometries, and I shall apply the theory to examine the role of chaperones in promoting accurate assembly. These theoretical predictions will be tested with two case studies of speci?c model systems. This work will lead to an improved understanding of regulation at the proteomic level. A physically rigorous theory will establish general principles of the self-assembly of macromolecular complexes. Understanding the mechanisms of chaperone-assisted self-assembly will also enable the rational engineering of biomimetic chaperones, which hold great potential for altering the production of complexes in vivo, thus guiding the development of therapeutic strategies for a wide range of protein-misassembly disorders.
Proteins and nucleic acids possess the remarkable ability to assemble into speci?c, modular structures known as complexes that are essential for a wide range of biological functions. Although breakdowns in the regulation of this process are associated with many protein-misassembly disorders, the molecular mechanisms by which complexes self-assemble in the cell are currently not well understood. The aim of this work is to identify the physical principles governing self-assembly in the cell, which may lead to new therapeutic strategies for counteracting protein misassembly.
| Sajfutdinow, Martin; Jacobs, William M; Reinhardt, Aleks et al. (2018) Direct observation and rational design of nucleation behavior in addressable self-assembly. Proc Natl Acad Sci U S A 115:E5877-E5886 |
| Jacobs, William M; Shakhnovich, Eugene I (2017) Evidence of evolutionary selection for cotranslational folding. Proc Natl Acad Sci U S A 114:11434-11439 |
| Jacobs, William M; Shakhnovich, Eugene I (2016) Structure-Based Prediction of Protein-Folding Transition Paths. Biophys J 111:925-36 |
