Biomolecular binding is ubiquitous and central to biological function. However, the detailed molecular mechanisms by which, e.g., small molecules bind to DNA and proteins interact with other proteins, are not well understood. The tremendous computational power of graphics processor units (GPUs) combined with advanced sampling algorithms such as weighted ensemble (WE) offers the opportunity to use molecular dynamics (MD) to simulate such binding processes directly. Moreover, harvesting and analyzing a statistically meaningful ensemble of binding events allows for unprecedented mechanistic understanding. Here, we have applied WE to simulate the binding of the Hoechst 33258 minor groove ligand to double-stranded DNA and the complexation of a peptide-bound major histocompatibility complex (pMHC) protein with a T cell receptor (TCR) protein. The simulations reveal new insights about specific biomolecular and hydration dynamics involved in the binding processes.

Elucidating biomolecular binding mechanisms with weighted ensemble simulations

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ACS Fall 2022

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