Conformational Dynamics and Allostery of Supramolecular Protein Assemblies: from the Nuclear Pore Complex to GroEL

Abstract

Supramolecular protein assemblies participate in a broad range of cellular functions including transcription, translation, protein synthesis and folding, translocation of biomolecules, and cell division. Single particle cryo-electron microscopy is increasingly revealing the structure of diverse high molecular weight protein assemblies at ever higher resolution. While the static structure of these assemblies provides invaluable insight into their functional mechanism, important additional information is provided by their conformational dynamics. Here we present an unsupervised computational framework that is used to analyze the conformational dynamics of the majority of structures deposited in the Electron Microscopy Data Bank. Conformational dynamics are computed using normal mode analysis based on a recently established finite element framework, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the nuclear pore complex from Dictyostelium discoideum and the chaperonin GroEL from Escherichia coli, revealing regions that are important to the stability of these molecules, as well as highly coupled dynamically in collective molecular motions. Results are publically available at http://www.cdyn.org and will be extended to include proteins in the Protein Data Bank, offering an important source of dynamical information that may be used to investigate the biological function of a broad range of molecules.