The glassy state of crambin and the THz time scale protein-solvent fluctuations possibly related to protein function

G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin. This approach allows us to examine the role of conformational heterogeneity in the selection and stabilization of specific signaling pathways in the photo-activation of the receptor. We demonstrate that ligand-induced shifts in the conformational equilibrium prompt vibrational resonances in the protein structure that link the dynamics of conserved interactions with fluctuations of the active-state ligand. The connection of vibrational modes creates an allosteric association of coupled fluctuations that forms a coherent signaling pathway from the receptor ligand-binding pocket to the G-protein activation region. Our evolutionary analysis of rhodopsin-like GPCRs suggest that specific allosteric sites play a pivotal role in activating structural fluctuations that allosterically modulate functional signals.

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“…3b. Above 160 cm −1 the experimental spectrum is dominated by modes that describe hydration and bulk water intermolecular interactions5354.…”

Section: Resultsmentioning

confidence: 99%

Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors

Woods

Dutta

Klein‐Seetharaman

2016

Sci Rep

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“…Fourier transforms FTs are used to calculate frequency spectra for time series extracted from these simulations. One example is the frequency spectrum for the velocity autocorrelation function VACF, which can point to interaction mechanisms of correlated motions in a protein . Another example is the frequency spectrum for the water hydrogen‐bond time autocorrelation function HBACF which provides information about the structure of the hydration shell surrounding the protein .…”

Section: Introductionmentioning

confidence: 99%

“…One example is the frequency spectrum for the velocity autocorrelation function VACF, which can point to interaction mechanisms of correlated motions in a protein. [2][3][4][5][6] Another example is the frequency spectrum for the water hydrogen-bond time autocorrelation function HBACF which provides information about the structure of the hydration shell surrounding the protein. 6 However, this use of FTs assumes that the time series being analyzed are stationary, linear, and have dynamics that do not reside in a high dimensional space.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6] Another example is the frequency spectrum for the water hydrogen-bond time autocorrelation function HBACF which provides information about the structure of the hydration shell surrounding the protein. 6 However, this use of FTs assumes that the time series being analyzed are stationary, linear, and have dynamics that do not reside in a high dimensional space. 7 When one or more of these conditions are not met, a suitable alternative approach should be used to calculate frequency spectra from the corresponding time series.…”

Section: Introductionmentioning

confidence: 99%

“…8,28-30 Frequencies <0. 6 THz fall into what is known as the relaxation region, and are attributed to the rattling motions of a structural unit in a cage formed by its neighbors. 31,32 Recently, the coupling between a protein and its surrounding hydration shell, and the effect of this coupling on the vibration spectrum of the water hydrogen bond network, has been investigated in the THz frequency regime, which also includes the frequency range of large amplitude modes of proteins.…”

Section: Introductionmentioning

confidence: 99%

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THz frequency spectrum of protein–solvent interaction energy using a recurrence plot‐based Wiener–Khinchin method

Karain

2016

Proteins

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The dynamics of a protein and the water surrounding it are coupled via nonbonded energy interactions. This coupling can exhibit a complex, nonlinear, and nonstationary nature. The THz frequency spectrum for this interaction energy characterizes both the vibration spectrum of the water hydrogen bond network, and the frequency range of large amplitude modes of proteins. We use a Recurrence Plot based Wiener-Khinchin method RPWK to calculate this spectrum, and the results are compared to those determined using the classical auto-covariance-based Wiener-Khinchin method WK. The frequency spectra for the total nonbonded interaction energy extracted from molecular dynamics simulations between the β-Lactamase Inhibitory Protein BLIP, and water molecules within a 10 Å distance from the protein surface, are calculated at 150, 200, 250, and 310 K, respectively. Similar calculations are also performed for the nonbonded interaction energy between the residues 49ASP, 53TYR, and 142PHE in BLIP, with water molecules within 10 Å from each residue respectively at 150, 200, 250, and 310 K. A comparison of the results shows that RPWK performs better than WK, and is able to detect some frequency data points that WK fails to detect. This points to the importance of using methods capable of taking the complex nature of the protein-solvent energy landscape into consideration, and not to rely on standard linear methods. In general, RPWK can be a valuable addition to the analysis tools for protein molecular dynamics simulations. Proteins 2016; 84:1549-1557. © 2016 Wiley Periodicals, Inc.

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Peptide-Protein Binding Investigated by Far-IR Spectroscopy and Molecular Dynamics Simulations

Cote¹,

Nominé²,

Ramírez³

et al. 2017

Biophysical Journal

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Molecular dynamics (MD) simulations and far-infrared (far-IR) spectroscopy were combined to study peptide binding by the second PDZ domain (PDZ1) of MAGI1, which has been identified as an important target for the Human Papilloma Virus. PDZ1 recognizes and binds to the C-terminal end of the E6 protein from high-risk Human Papilloma Virus. The far-IR spectra of two forms of the protein, an unbound APO form and a HOLO form (where the PDZ1 is bound to an 11-residue peptide derived from the C terminus of HPV16 E6), were obtained. MD simulations were used to determine the most representative structure of each form and these were used to compute their respective IR spectra by normal mode analysis. Far-UV circular dichroism spectroscopy was used to confirm the secondary structure content and the stability through temperature-dependent studies. Both the experimental and calculated far-IR spectra showed a red shift of the low-frequency peaks upon peptide binding. The calculations show that this is coincident with an increased number of hydrogen bonds formed as the peptide augments the protein β-sheet. We further identified the contribution of surface-bound water molecules to bands in the far-IR and, through the calculations, identified potential pathways for allosteric communication. Together, these results demonstrate the utility of combining far-IR experiments and MD studies to study peptide binding by proteins.

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The glassy state of crambin and the THz time scale protein-solvent fluctuations possibly related to protein function

Cited by 14 publications

References 70 publications

Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors

Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors

THz frequency spectrum of protein–solvent interaction energy using a recurrence plot‐based Wiener–Khinchin method

Peptide-Protein Binding Investigated by Far-IR Spectroscopy and Molecular Dynamics Simulations

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