期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 41, 页码 20446-20452出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1907251116
关键词
intrinsically disordered protein; MD simulation; small-angle scattering; conformational ensemble; transient helices
资金
- Laboratory Directed Research and Development Program of Oak Ridge National Laboratory
- Office of Biological & Environmental Research in the Department of Energy (DOE) Office of Science (BER) [ERKP300]
- BER
- National Energy Research Scientific Computing Center [DE-AC02-05CH11231]
- Oak Ridge Leadership Computing Facility [DE-AC05-00OR22725]
- US DOE [DE-AC05-00OR22725]
Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.
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