Intrinsically disordered proteins (IDPs) play a critical role in various cellular functions and are associated with multiple diseases. However, a detailed structural characterization of IDPs, via the generation of an accurate ensemble of 3D structures, remains an immense challenge in structural biology. In recent years, attempts to determine the configurational ensemble of IDPs computationally have been hitherto hampered by the necessity of re-weighting or biasing molecular dynamics (MD) simulations to match experimental observables. Such operations often reduce the precision of the generated model because different structural ensembles may yield the same experimental observable, “a degeneracy problem”. In my talk, I will present how enhanced sampling MD can accurately reproduce multiple experimental ensemble-averaged observables, such as small-angle X-ray/neutron scattering, nuclear magnetic resonance chemical shifts, and circular dichroism spectrum of the 95 residues long disordered N-terminal domain of c-Src kinase (SH4UD) without re-weighting or constraining the simulations. Our simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which resembles heterogeneous structures that cannot be described by simple polymer theory (Flory exponent). Moreover, we observed that SH4UD adopts transient helices, which are found away from known phosphorylation sites but overlap with lipid-binding sites and could play a key role in the stabilization of structural regions necessary for phosphorylation and binding to the cell membrane. Our findings indicate that an adequately-sampled ensemble of structures using enhanced sampling MD can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.

Modeling an ensemble of intrinsically disordered protein using enhanced sampling molecular dynamics simulations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.