Real Time Observation of Ultrafast Peptide Conformational Dynamics: Molecular Dynamics Simulation vs Infrared Experiment

Nguyen, Phuong H.; Staudt, Heike; Wachtveitl, Josef; Stock, Gerhard

doi:10.1021/jp207945p

Cited by 13 publications

(15 citation statements)

References 50 publications

(97 reference statements)

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“…13 In fact, accompanying nonequilibrium MD calculations of bcAMPBw in explicit water have shown that the photoinduced conformational changes of the peptide are quite complex. 12 In nice agreement with experiment, it was found that some commonly used indicators to monitor global conformational change, such as the radius of gyration and the root-mean-square deviation, indeed show time scales of 4 and 200 ps. Calculating the time evolution of the backbone dihedral angles φ and ψ of the individual residues, though, typically resulted in much longer response times.…”

Section: Introductionsupporting

confidence: 64%

“…While the details of the experimental transient IR spectrum of bcAMPBw are indeed different, nevertheless, quite small frequency shifts (≈2 cm −1 ) and surprisingly short product rise times (≈5 ps) upon cis → trans isomerization have been found. 12 The situation is very similar for bcAMPB in DMSO. 9…”

Section: B Transient Spectramentioning

confidence: 90%

“…12 and are reviewed here only briefly. All simulations were performed with the GROMACS program suite, 25 11 and placed in an octahedral box containing ≈1500 water molecules.…”

Section: A MD Simulationsmentioning

confidence: 99%

“…1. A recent timeresolved IR study 12 has shown that this photoswitchable peptide, henceforth termed bcAMPBw, exhibits conformational dynamics on (at least) three time scales: 0.2 ps for the initial cis → trans photoisomerization of azobenzene, 5 ps for the cooling of the photoexcited system in water, as well as 5 and 300 ps time scales that were assigned to reflect the photoinduced conformational rearrangement of the peptide. a) Electronic mail: stock@physik.uni-freiburg.de.…”

Section: Introductionmentioning

confidence: 99%

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Simulation of transient infrared spectra of a photoswitchable peptide

Kobus

Lieder

Nguyen

et al. 2011

The Journal of Chemical Physics

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In transient infrared (IR) experiments, a molecular system may be photoexcited in a nonstationary conformational state, whose time evolution is monitored via IR spectroscopy with high temporal and structural resolution. As a theoretical formulation of these experiments, this work derives explicit expressions for transient one- and two-dimensional IR spectra and discusses various levels of approximation and sampling strategies. Adopting a photoswitchable octapeptide in water as a representative example, nonequilibrium molecular dynamics simulations are performed and the photoinduced conformational dynamics and associated IR spectra are discussed in detail. Interestingly, it is found that the time scales of dynamics and spectra may differ from residue to residue by up to an order of magnitude. Considering merely the cumulative spectrum of all residues, the contributions of the individual residues largely compensate each other, which may explain the surprisingly small frequency shifts and short photoproduct rise times found in experiment. Even when a localized amide I mode is probed (e.g., via isotope labeling), the vibrational frequency shift is shown to depend in a complicated way on the conformation of the entire peptide as well as on the interaction with the solvent. In this context, various issues concerning the interpretation of transient IR spectra and conformational dynamics in terms of a few exponential time scales are discussed.

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Section: Introductionsupporting

confidence: 64%

Section: B Transient Spectramentioning

confidence: 90%

“…12 and are reviewed here only briefly. All simulations were performed with the GROMACS program suite, 25 11 and placed in an octahedral box containing ≈1500 water molecules.…”

Section: A MD Simulationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Simulation of transient infrared spectra of a photoswitchable peptide

Kobus

Lieder

Nguyen

et al. 2011

The Journal of Chemical Physics

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“…[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. The photoswitch was attached at residues 21 and 76 of PDZ2 ( Figure Figure 1), because the C α distances between these anchor residues in the free and bound state closely match the linear extension of the photoswitch in the cis and the trans state, respectively.…”

Section: Introductionmentioning

confidence: 99%

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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How Photoisomerization Drives Peptide Folding and Unfolding: Insights from QM/MM and MM Dynamics Simulations

et al. 2016

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Photoswitchable azobenzene cross-linkers can control the folding and unfolding of peptides by photoisomerization and can thus regulate peptide affinities and enzyme activities.U sing quantum mechanics/molecular mechanics (QM/MM) methods and classical MM force fields,w er eport the first molecular dynamics simulations of the photoinduced folding and unfolding processes in the azobenzene crosslinked FK-11 peptide.Wefind that the interactions between the peptide and the azobenzene cross-linker are crucial for controlling the evolution of the secondary structure of the peptide and responsible for accelerating the folding and unfolding events.T hey also modify the photoisomerization mechanism of the azobenzene cross-linker compared with the situation in vacuo or in solution.Anefficient light-sensitive peptide can be constructed by cross-linking aphotoswitchable small cross-linker molecule to the peptide backbone;photoinduced structural changes of the cross-linker can trigger reversible changes in peptide conformations.T his kind of photoresponse can provide an avenue for probing and manipulating complex living systems.[1] Thep hotoinduced conformational dynamics of peptides with built-in azobenzenes has been exploited to probe functional changes of proteins,t omanipulate enzyme activities,a nd to control cell signaling.[2] However,adetailed mechanistic understanding of these processes at the atomistic level is still lacking.Experimentally,t ime-resolved infrared spectroscopy was employed to monitor the conformational dynamics of crosslinked peptides;itwas found that both folding and unfolding processes show complex spectral kinetics and strongly depend on the photoexcitation wavelength and on temperature. [3] Computationally,a zobenzene-linked peptides were explored by classical molecular dynamics (MD) simulations.[4] However,i nt hese studies,t he initial nonadiabatic photoisomerization was not considered or was only simulated using as imple model potential, and the effects of the photoisomerization on the subsequent conformational dynamics of peptides were not investigated;m oreover,o nly the photoinduced folding dynamics was simulated in those studies. [4] Theu nfolding dynamics of cross-linked peptides has rarely been explored experimentally because peptide unfolding processes are generally endothermic and difficult to study. [4f] Asalient dynamical feature of these cross-linked peptides is that their folding and unfolding processes are significantly accelerated compared with peptides without cross-linkers. [3a] This speedup must originate from the interaction between the cross-linker and the peptide.Athorough understanding of this interplay is crucial to rationalize the folding and unfolding dynamics of cross-linked peptides,t os elect appropriate cross-linkers,t ooptimize cross-linking positions,a nd eventually to control these photoinduced conformational changes. It is difficult to obtain detailed information on these interactions solely from experiment, and it is thus desirable to perform th...

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Real Time Observation of Ultrafast Peptide Conformational Dynamics: Molecular Dynamics Simulation vs Infrared Experiment

Cited by 13 publications

References 50 publications

Simulation of transient infrared spectra of a photoswitchable peptide

Simulation of transient infrared spectra of a photoswitchable peptide

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

How Photoisomerization Drives Peptide Folding and Unfolding: Insights from QM/MM and MM Dynamics Simulations

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