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Frequency Response of a Protein to Local Conformational Perturbations | PLOS Computational Biology

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Author Summary Similar to a machine in which interactions between different parts determine its function, signaling between the residues of a protein may play an important role in determining its function. External perturbations, such as ligand binding to a local region, may trigger a global response of the protein, manifested as perturbations in positions or mobility of atoms. Here we introduce a frequency response technique, in which a local periodic perturbation is employed on a flexible loop of a protein, and atomic responses are analyzed. Protein response characteristics are found to be closely related to perturbation frequency, so frequency analysis tools such as power spectral densities and magnitude Bode plots are utilized. Conformational change of the protein estimated by this method is found to be consistent with that determined from crystal structures. We cluster the phase angles of side-chains dihedral angles to identify collectively fluctuating residues, and determine a large number of hydrophobic interactions, which help intraprotein signal propagation. We believe that the suggested frequency response technique will be a fine contribution to the existing repertoire of perturbation methods.

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Signals created by local perturbations are known to propagate long distances through proteins via backbone connectivity and nonbonded interactions. In the current study, signal propagation from the flexible ligand binding loop to the rest of Protein Tyrosine Phosphatase 1B (PTP1B) was investigated using frequency response techniques. Using restrained Targeted Molecular Dynamics (TMD) potential on WPD and R loops, PTP1B was driven between its crystal structure conformations at different frequencies. Propagation of the local perturbation signal was manifested via peaks at the fundamental frequency and upper harmonics of 1/f distributed spectral density of atomic variables, such as Cα atoms, dihedral angles, or polar interaction distances. Frequency of perturbation was adjusted high enough (simulation length >∼10×period of a perturbation cycle) not to be clouded by random diffusional fluctuations, and low enough (<∼0.8 ns−1) not to attenuate the propagating signal and enhance the contribution of the side-chains to the dissipation of the signals. Employing Discrete Fourier Transform (DFT) to TMD simulation trajectories of 16 cycles of conformational transitions at periods of 1.2 to 5 ns yielded Cα displacements consistent with those obtained from crystal structures. Identification of the perturbed atomic variables by statistical t-tests on log-log scale spectral densities revealed the extent of signal propagation in PTP1B, while phase angles of the filtered trajectories at the fundamental frequency were used to cluster collectively fluctuating elements. Hydrophobic interactions were found to have a higher contribution to signal transduction between side-chains compared to the role of polar interactions. Most of in-phase fluctuating residues on the signaling pathway were found to have high identity among PTP domains, and located over a wide region of PTP1B including the allosteric site. Due to its simplicity and efficiency, the suggested technique may find wide applications in identification of signaling pathways of different proteins.

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Crystal structure,Dihedral angles,Eigenvectors,Frequency response,Biochemical simulations,Molecular dynamics,Principal component analysis,Signal transduction

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https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003238

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Frequency Response of a Protein to Local Conformational Perturbations

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Author Summary Similar to a machine in which interactions between different parts determine its function, signaling between the residues of a protein may play an important role in determining its function. External perturbations, such as ligand binding to a local region, may trigger a global response of the protein, manifested as perturbations in positions or mobility of atoms. Here we introduce a frequency response technique, in which a local periodic perturbation is employed on a flexible loop of a protein, and atomic responses are analyzed. Protein response characteristics are found to be closely related to perturbation frequency, so frequency analysis tools such as power spectral densities and magnitude Bode plots are utilized. Conformational change of the protein estimated by this method is found to be consistent with that determined from crystal structures. We cluster the phase angles of side-chains dihedral angles to identify collectively fluctuating residues, and determine a large number of hydrophobic interactions, which help intraprotein signal propagation. We believe that the suggested frequency response technique will be a fine contribution to the existing repertoire of perturbation methods.

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https://journals.plos.org/ploscompbiol/article/figure/image?id=10.1371/journal.pcbi.1003238.g006&size=inline

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Frequency Response of a Protein to Local Conformational Perturbations

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Frequency Response of a Protein to Local Conformational Perturbations

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