Dynamically driven correlations in elastic net models reveal sequence of
events and causality in proteins
Abstract
Protein dynamics orchestrate allosteric regulation, but elucidating the
sequence of events and causal relationships within these intricate
processes remains challenging. We introduce the Dynamically Perturbed
Gaussian Network Model (DP-GNM), a novel approach that uncovers the
directionality of information flow within proteins. DP-GNM leverages
time-dependent correlations to achieve two goals: identifying driver and
driven residues and revealing communities of residues exhibiting
synchronized dynamics. Applied to wild type and mutated structures of
Cyclophilin A, DP-GNM unveils a hierarchical network of information
flow, where key residues initiate conformational changes that propagate
through the protein in a directed manner. This directional causality
illuminates the intricate relationship between protein dynamics and
allosteric regulation, providing valuable insights into protein function
and potential avenues for drug design. Furthermore, DP-GNM’s potential
to elucidate dynamics under periodic perturbations like the circadian
rhythm suggests its broad applicability in understanding complex
biological processes governed by environmental cycles.