Intrinsically disordered proteins (IDPs) lack stable structures under physiological conditions. They have been suggested to play pivotal roles in cellular signaling and regulation and are associated with many human diseases. Despite the importance of elucidating IDP structure-function relationships, it’s very challenging to characterize the heterogeneous structural ensembles of IDPs. Recently, we have developed a method called multiscale enhanced sampling (MSES) to accelerate atomistic simulations of IDPs by coupling with efficient coarse-grained (CG) models. To further maximize the sampling efficiency of MSES, the CG model should be able to generate fast local and long-range structural fluctuations that are consistent with atomistic simulations. Meanwhile, new strategies need to be developed to allow effective communication of structural dynamics between the two levels. Here, we will present developments of better CG models and improved MSES protocols for more efficient simulations of IDPs and protein conformations in general. Application of these strategies to characterize the structural ensemble of a few non-trivial IDPs has shown faster conformational transition rate and convergence rate compared with temperature replica exchange and original MSES simulations.

Multiscale enhanced sampling of intrinsically disordered protein conformations

256th National Meeting (2018)

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