Abstract
Intra-molecular energy transport between distant functional sites plays important roles in allosterically regulating the biochemical activity of proteins. How to identify the specific intra-molecular signaling pathway from protein tertiary structure remains a challenging problem. In the present work, a non-equilibrium dynamics method based on the elastic network model (ENM) was proposed to simulate the energy propagation process and identify the specific signaling pathways within proteins. In this method, a given residue was perturbed and the propagation of energy was simulated by non-equilibrium dynamics in the normal modes space of ENM. After that, the simulation results were transformed from the normal modes space to the Cartesian coordinate space to identify the intra-protein energy transduction pathways. The proposed method was applied to myosin and the third PDZ domain (PDZ3) of PSD-95 as case studies. For myosin, two signaling pathways were identified, which mediate the energy transductions form the nucleotide binding site to the 50 kDa cleft and the converter subdomain, respectively. For PDZ3, one specific signaling pathway was identified, through which the intra-protein energy was transduced from ligand binding site to the distant opposite side of the protein. It is also found that comparing with the commonly used cross-correlation analysis method, the proposed method can identify the anisotropic energy transduction pathways more effectively.
Highlights
Energy transport through specific pathways in proteins enables the communication between different parts of the molecule, which is thought to play important roles in many functional processes of proteins
The signaling pathways in myosin revealed by the Gaussian network model (GNM)-based non-equilibrium dynamics method
A non-equilibrium dynamics method based on elastic network model (ENM) was proposed to simulate the energy propagation process and identify the specific signaling pathways within proteins
Summary
Energy transport through specific pathways in proteins enables the communication between different parts of the molecule, which is thought to play important roles in many functional processes of proteins. Ishikura and Yamato developed a theoretical method based on the long-time equilibrium MD simulations to analyze the pathways of inter-residue energy flow between different regions in proteins. Non-equilibrium MD simulation method, called as anisotropic thermal diffusion, to detect the intramolecular signaling pathways In their method, the probed residues or atoms are coupled to a higher temperature, serving as the energy source, whereas the temperature couplings for other atoms in the protein are turned off. A non-equilibrium dynamics method was proposed based on ENM to simulate the energy transduction, which is a non-equilibrium process, in proteins. A residue in the ATP binding site was perturbed and the specific signaling pathway responsible for the allosteric regulation of the protein functions was identified. Our prediction results are consistent with the available experimental and simulation data
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