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This study integrates transient infrared spectroscopy with nonequilibrium molecular dynamics simulations to elucidate the molecular motions that underlie protein dynamics observed in time-resolved infrared spectra. By focusing on single-domain allosteric proteins, the authors identify inter-residue contact distances as the most accurate structural representation of experimental dynamics, revealing localized networks of coordinated contacts that facilitate communication between secondary-structure elements. The findings quantitatively link characteristic timescales of these contact networks to experimentally observed relaxation processes, providing a comprehensive framework for understanding protein dynamics at an atomic level.
Inter-residue contact distances reveal the hidden molecular motions driving protein dynamics, bridging the gap between experimental spectroscopy and molecular simulations.
Time-resolved infrared spectroscopy probes protein dynamics over timescales spanning more than ten orders of magnitude, yet the molecular motions underlying the observed kinetic signatures have remained elusive. Here we combine transient infrared spectroscopy with nonequilibrium molecular dynamics simulations to establish a direct connection between experimental relaxation times and local structural motions. Studying single-domain allosteric proteins, we find that inter-residue contact distances provide the structural representation that most faithfully reproduces the experimental dynamics. Correlation analysis identifies localized networks of coordinated contacts that mediate communication between secondary-structure elements. The characteristic timescales of these contact networks quantitatively match the experimentally observed relaxation processes, enabling each kinetic step to be assigned to a specific molecular motion. Applied to allosteric signal propagation in PDZ3 and photoinduced ligand unbinding in PDZ2, this framework provides an atomistic picture of hierarchical protein relaxation and establishes a general framework for connecting transient infrared spectroscopy with the molecular mechanisms of protein dynamics.
