Many proteins involved in cellular signaling and regulation appear to exist at the thermodynamic stability and instability boundary, such that the disordered ensembles are poised to respond sensitively to various cellular signals including changes in the cellular environment, binding of small and big co-factors, and post-translational modifications. There is thus a great need to determine the detailed properties of these intrinsically disordered proteins (IDPs), such that one can start to relate these properties to function and understand how the ensemble-function relationship maybe perturbed in human diseases. I will present recent progresses from my lab to leverage efficient implicit treatment of solvent for reliable atomistic simulations of disordered protein ensembles. In particular, development of a multi-scale enhanced sampling (MSES) technique has enable us to re-optimize a generalized Born with molecular volume (GBMV) implicit solvent force field, which can now recapitulate the stability and structure of a wide range of helical and beta-hairpin peptides. Importantly, the new force field is largely free of the over-compaction problem. A GPU-accelerated version of GMBV was recently implemented within the CHARMM/OpenMM platform to provide ~70-fold speedup compared to the single-CPU version. Availability of an efficient and accurate implicit solvent protein force field paves the way interogating the ensemble-function-disease relationship of many important IDPs at the atomistic level.

Implicit solvent for efficient exploration of disordered protein energy landscape

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.