Kinetic response of a photoperturbed allosteric protein

Buchli, Brigitte; Waldauer, Steven A.; Walser, Reto; Donten, Mateusz L.; Pfister, Rolf; Blöchliger, Nicolas; Steiner, Sandra; Caflisch, Amedeo; Zerbe, Oliver; Hamm, Peter

doi:10.1073/pnas.1306323110

Cited by 101 publications

(179 citation statements)

References 64 publications

(64 reference statements)

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“…The initial configuration of PDZ2S-cis and -trans were taken from Buchli et al 45 (PDB entries 2M0Z and 2M10). Compared to the wild-type protein, PDZ2S contains an additional glycine residue at the N-terminus (residue 0), residues Ser-21 and Glu-76 were mutated into cysteines which are covalently attached to the azobenzene photoswitch, and two residues (Pro-95 and Thr-96) were appended at the C-terminus.…”

Section: Methods Simulation Set-upmentioning

confidence: 99%

“…Results and discussion Figure Figure 2 shows the distribution of root mean square deviations (rmsd) of configurations of PDZ2S-cis and -trans with respect to the corresponding NMR structures, 45 as well as the rmsd of configurations of PDZ2-free and -bound with respect to the corresponding x-ray structures. 16 PDZ2-free shows a bimodal distribution, indicating (at least) two conformational substates.…”

Section: Analysis Methodsmentioning

confidence: 99%

“…16 The nature of the subsequent ligand-induced intramolecular signaling process, however, remains a matter of debate, although various proposals of signaling pathways exist. [30][31][32][33][34][35][36][37][38] To facilitate a dynamic perspective of the allosteric mechanism, recently Buchli et al 45 presented a time-resolved study of the transition from the free to the bound state of PDZ2 triggered by a molecular photoswitch. [46][47][48][49][50][51] By covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that affects the cis → trans photoisomerization of azobenzene, they were able to initiate a conformational change similar to the free-bound transition.…”

Section: Introductionmentioning

confidence: 99%

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Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein. October 9, 2014 * To whom correspondence should be addressed 1 Abstract A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.

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Section: Methods Simulation Set-upmentioning

confidence: 99%

Section: Analysis Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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“…NMR spectroscopy can elucidate dynamics on many timescales, even down into the picosecond regime, but it does so via relaxation experiments, which works only for equilibrium fluctuations. With "direct time resolution", we have in mind to study non-equilibrium processes in a pump-probe fashion, such as the triggered (un)folding of a protein [4][5][6][7][8][9][10][11] or the propagation of a perturbation through an allosteric system [12][13][14]. The direct time resolution of a spectroscopic method is dictated by the dephasing time of its transitions, which is a few picoseconds for typical vibrational bands in the solution phase, in contrast to millisecond dephasing of NMR.…”

Section: Infrared Spectroscopy Of Proteinsmentioning

confidence: 99%

“…The protein should have only one of these amino acids at the desired position, and in this regard, Met is advantageous as it is relatively rare in natural proteins, whereas His is often crucial for their function. Note that we have disregarded cysteine as another possible anchor point for a label [29], since we want to keep that amino acid free for adding other functionalities, such as a photoswitch [6,8,12,13,59] used to initiate a non-equilibrium process (see the example highlighted below). We reiterate that being able to initiate a non-equilibrium process is a prerequisite to extend the accessible time window beyond the vibrational lifetime of the label.…”

Section: Advancing the Selectivitymentioning

confidence: 99%

Fast infrared spectroscopy of protein dynamics: advancing sensitivity and selectivity

Koziol

Johnson

Stucki-Buchli

et al. 2015

Current Opinion in Structural Biology

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2D-IR spectroscopy has matured to a powerful technique to study the structure and dynamics of peptides, but its extension to larger proteins is still in its infancy, the major limitations being sensitivity and selectivity. Site-selective information requires measuring single vibrational probes at sub-millimolar concentrations where most proteins are still stable, which is a severe challenge for conventional (FT)IR spectroscopy. Besides its ultrafast time-resolution, a so far largely underappreciated potential of 2D-IR spectroscopy lies in its sensitivity gain. The present paper sets the goals and outlines strategies how to use that sensitivity gain together with properly designed vibrational labels to make IR spectroscopy a versatile tool to study a wide class of proteins. Abstract Abstract: 2D-IR spectroscopy has matured to a powerful technique to study the structure

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Mapping Energy Transport Networks in Proteins

Leitner

Yamato

2018

Reviews in Computational Chemistry

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INTRODUCTIONThe response of proteins to chemical reactions or impulsive excitation that occurs within the molecule has fascinated chemists for decades. [1][2][3] In recent years ultrafast X-ray studies have provided ever more detailed information about the evolution of protein structural change following ligand photolysis, 4-5 and time-resolved IR and Raman techniques, e.g., have provided detailed pictures of the nature and rate of energy transport in peptides and proteins, [6][7][8][9][10][11] including recent advances in identifying transport through individual amino acids of several heme proteins. [12][13][14] Computational tools to locate energy transport pathways in proteins have also been advancing. 15 Energy transport pathways in proteins have since some time been identified by molecular dynamics (MD) simulations, [16][17] and more recent efforts have focused on the development of coarse graining approaches, 18-29 some of which have exploited analogies to thermal transport in other molecular materials. [30][31][32][33][34][35] With the identification of pathways in proteins and protein 2 complexes, network analysis has been applied to locate residues that control protein dynamics and possibly allostery, [36][37][38] where chemical reactions at one binding site mediate reactions at distance sites of the protein. In this chapter we review approaches for locating computationally energy transport networks in proteins. We present background into energy and thermal transport in condensed phase and macromolecules that underlies the approaches we discuss before turning to a description of the approaches themselves. We also illustrate the application of the computational methods for locating energy transport networks and simulating energy dynamics in proteins with several examples.One of the themes that we address in this chapter is the difference between energy transport in condensed phase generally and in a folded polymer such as a protein specifically. While the approaches that we present and detail are based on linearresponse theory for transport, we apply them to a system, a protein, where energy transport occurs highly anisotropically.We are mainly concerned with the characterization of such anisotropic transport, not simply the calculation of transport coefficients for a particular object, though that information can also be calculated starting with the approaches we present. The focus here then is on local energy transport coefficients, such as local energy conductivities and diffusivities, as discussed below, and how these local transport properties connect into a network that mediates energy dynamics in the protein. It is the network of such local energy transport coefficients that, once identified and located, can be used to model the global energy dynamics in a protein, as we describe.That energy transport pathways exist, i.e., energy does not simply flow isotropically through a globular protein, is an inherent property of the geometry of a 3 folded protein, [62][63][64][65][66][67][68][69][70] which i...

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Kinetic response of a photoperturbed allosteric protein

Cited by 101 publications

References 64 publications

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

Fast infrared spectroscopy of protein dynamics: advancing sensitivity and selectivity

Mapping Energy Transport Networks in Proteins

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