Framework for Quantifying the Efficiency of Competing Signal Transmission Modes in Proteins

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Biological signal transmission relies on protein structural changes.
• Microscopic details of protein signal transmission remain unclear.
• Allosteric proteins utilize sensor and effector modules for signaling.

Purpose of the Study:

• To develop a theoretical framework for analyzing signal transmission through proteins.
• To define frequency-dependent force and displacement transmit functions.
• To quantify how local perturbations propagate through viscoelastic media like proteins.

Main Methods:

• Developed a theoretical framework based on linear-response theory.
• Defined frequency-dependent transmit functions using equilibrium fluctuations.
• Applied the framework to all-atom molecular dynamics simulations.
• Analyzed simulations of a bacterial histidine kinase and the β2-adrenergic receptor.

Main Results:

• Identified shift, splay, and twist deformation modes for signal propagation in a coiled-coil (CC) motif.
• Confirmed signal propagation through the CC motif via simulations.
• Inferred splay deformation as the most biologically relevant mode for histidine kinase function.
• Compared signal transmission across structural domains of the β2-adrenergic receptor.

Conclusions:

• The developed framework effectively quantifies signal transmission in proteins.
• Specific deformation modes play critical roles in protein-mediated signaling.
• Splay deformation is a key mechanism in histidine kinase signaling.
• Understanding signal transmission is vital for deciphering complex biological pathways.