Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories.

Molecular interactions are essential for regulation of cellular processes from the formation of multi-protein complexes to the allosteric activation of enzymes. Identifying the essential residues and molecular features that regulate such interactions is paramount for understanding the biochemical process in question, allowing for suppression of a reaction through drug interventions or optimization of a chemical process using bioengineered molecules. In order to identify important residues and information pathways within molecular complexes, the dynamical network analysis method was developed and has since been broadly applied in the literature. However, in the dawn of exascale computing, this method is frequently limited to relatively small biomolecular systems. In this work, we provide an evolution of the method, application, and interface. All data processing and analysis are conducted through Jupyter notebooks, providing automatic detection of important solvent and ion residues, an optimized and parallel generalized correlation implementation that is linear with respect to the number of nodes in the system, and subsequent community clustering, calculation of betweenness of contacts, and determination of optimal paths. Using the popular visualization program visual molecular dynamics (VMD), high-quality renderings of the networks over the biomolecular structures can be produced. Our new implementation was employed to investigate three different systems, with up to 2.5M atoms, namely, the OMP-decarboxylase, the leucyl-tRNA synthetase complexed with its cognate tRNA and adenylate, and respiratory complex I in a membrane environment. Our enhanced and updated protocol provides the community with an intuitive and interactive interface, which can be easily applied to large macromolecular complexes.