Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session IX Abstracts

Restraining Molecular Dynamics and Modeling with Ion-Mobility Mass Spectrometry Erik Marklund , Matteo Degiacomi, Carol Robinson, Andrew Baldwin, Justin Benesch. University of Oxford, Oxford, United Kingdom. The dynamical variability of protein assemblies is a major stumbling block for structural biology and biophysical tools that provide only an ensemble average. Recent developments in ion mobility coupled to mass spectrometry (IM-MS) have rendered it an attractive new approach for studying the structure and dynamics of biomolecular complexes. From drift times measured by IM-MS the collisional cross sections (CCS) of proteins can be inferred, a single measurement reporting on all mass-separated species in a sample, such as multiple oligomeric states of polydisperse proteins. Since IM-MS separation takes place within milliseconds, the observed CCS distribution accurately represents the solution conditions. Furthermore, with the ability to perform time-resolved experiments, IM-MS is well suited for studying protein interactions and dynamics. As shown in this study, CCS hold structural information that is distinct from other geometric parameters of proteins, such as gyration radii. Making use of IM-MS data however requires computational modeling, for example comparison of CCS from candidate structures with those observed in experiments. This approach has been limited by the demanding calculation of macromolecular CCS. To overcome this limitation we have developed a new algorithm (IMPACT) for estimating CCS of structure models at unprecedented speed, with potential to transform the IM-MS-based modeling and for the first time allowing for directly restraining molecular dynamics simulations with IM-MS data. We have analyzed conformational ensembles and show how modern IM instrumentation is capable of assessing not only the structure of proteins, but also their conformational dynamics. Our analysis of all biological assemblies in the Protein Data Bank and other structural databases furthermore reveals how protein complexes of similar mass frequently have sufficiently different cross sections to be distinguishable by IM, which translates to proteome-wide applicability of IM-MS for the study of biomolecular structure and dynamics.

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