Combinatorial Coarse-Graining of Molecular Dynamics Simulations for Detecting Relationships between Local Configurations and Overall Conformations.

An automatic, multiscale, and three-dimensional (3D) summary of local configurations of the dynamics of proteins can help to discover and describe the relationships between different parts of proteins across spatial scales, including the overall conformation and 3D configurations of side chains and domains. These discoveries can improve our understanding of the function and allosteric mechanism of proteins and could potentially provide an avenue to test and improve the molecular mechanics force fields at different spatial resolutions. Many of the current methods are unable to effectively summarize shapes of 3D local configurations across all spatial scales. Here, we propose frequent substructure clustering (FSC) to fill this gap. Frequent substructure clustering of the Cβ atoms of the GB3 protein identifies six clusters of co-occurring local configurations. The clusters that are localized at different regions contribute to the overall conformation, and form two anticorrelating groups. The results suggest that FSC could describe dynamical relationships between different parts of proteins by providing a 3D description of the frequently occurring local configurations at different spatial resolutions. FSC could augment the use of other methods, such as Markov state models, to study the function of subcellular processes and highlight the role of local configurations in biomolecular systems.