Few-fs resolution of a photoactive protein traversing a conical intersection

Hosseinizadeh, Ahmad; Breckwoldt, Niels; Fung, Russell; Sepehr, Reyhaneh; Schmidt, Marius; Schwander, Peter; Santra, Robin; Ourmazd, A.

doi:10.1038/s41586-021-04050-9

Cited by 42 publications

(38 citation statements)

References 41 publications

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“… 27 and used in the context of time resolved experiments in Refs. 22 and 28 . Similar to LPSA, the overarching framework is that of a subspace projection preceded by time-lagged embedding and followed by modal decomposition.…”

Section: Comparison With Other Dynamics Retrieval Methodsmentioning

confidence: 99%

“…We map the incomplete data to a sparse-matrix representation, that is, we set any unmeasured component of

equal to zero. 22 With this choice, the fundamental issue that we need to address and mitigate is the stochastic weighting (by factors comprised between zero and one) of the underlying intensities, introduced by sparsity and partiality. To alleviate the effects of randomness, we project the data onto the subspace spanned by a set of trigonometric functions.…”

Section: Low-pass Spectral Analysismentioning

confidence: 99%

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Dynamics retrieval from stochastically weighted incomplete data by low-pass spectral analysis

Casadei

Hosseinizadeh

Schertler

et al. 2022

Structural Dynamics

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Time-resolved serial femtosecond crystallography (TR-SFX) provides access to protein dynamics on sub-picosecond timescales, and with atomic resolution. Due to the nature of the experiment, these datasets are often highly incomplete and the measured diffracted intensities are affected by partiality. To tackle these issues, one established procedure is that of splitting the data into time bins, and averaging the multiple measurements of equivalent reflections within each bin. This binning and averaging often involve a loss of information. Here, we propose an alternative approach, which we call low-pass spectral analysis (LPSA). In this method, the data are projected onto the subspace defined by a set of trigonometric functions, with frequencies up to a certain cutoff. This approach attenuates undesirable high-frequency features and facilitates retrieving the underlying dynamics. A time-lagged embedding step can be included prior to subspace projection to improve the stability of the results with respect to the parameters involved. Subsequent modal decomposition allows to produce a low-rank description of the system's evolution. Using a synthetic time-evolving model with incomplete and partial observations, we analyze the LPSA results in terms of quality of the retrieved signal, as a function of the parameters involved. We compare the performance of LPSA to that of a range of other sophisticated data analysis techniques. We show that LPSA allows to achieve excellent dynamics reconstruction at modest computational cost. Finally, we demonstrate the superiority of dynamics retrieval by LPSA compared to time binning and merging, which is, to date, the most commonly used method to extract dynamical information from TR-SFX data.

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Section: Comparison With Other Dynamics Retrieval Methodsmentioning

confidence: 99%

“…We map the incomplete data to a sparse-matrix representation, that is, we set any unmeasured component of

Section: Low-pass Spectral Analysismentioning

confidence: 99%

Dynamics retrieval from stochastically weighted incomplete data by low-pass spectral analysis

Casadei

Hosseinizadeh

Schertler

et al. 2022

Structural Dynamics

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“…At the 1 ps delay, we have refined the crystal structure of the tubulin-azo-CA4 complex in the predominant state but the electron density indicates that azo-CA4 has not yet reached a single conformation. With the experimental framework described here and recent progress in using machine learning to analyze ultrafast XFEL data ( 22 ), it seems now within reach to study the relevance of this heterogeneity to the isomerization mechanism with temporal resolutions of only few femtoseconds.…”

Section: Main Textmentioning

confidence: 99%

Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography

Wranik

Weinert

Slavov

et al. 2022

Preprint

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The dynamic interplay between proteins and their ligands is central to molecular biology, pharmacology, and drug development but is difficult to resolve experimentally. Using time-resolved serial crystallography at a synchrotron and X-ray laser, we studied the release of the photochemical affinity switch azo-Combretastatin A4 from the anti-cancer target tubulin. Thirteen logarithmically spaced temporal snapshots at near-atomic resolution are complemented by time-resolved spectroscopy and molecular dynamics simulations. They show how the photoinduced cis to trans isomerization of the azobenzene bond stretches the ligand in the picosecond to nanosecond range, followed by stepwise opening of a gating loop within microseconds, and completion of the unbinding reaction within milliseconds. Ligand unbinding is accompanied by collapse of the binding pocket and global tubulin-backbone rearrangements. Our results have implications for the molecular basis of photopharmacology, the mechanism of action of anti-tubulin drugs and provide a general experimental framework to study protein-ligand interaction dynamics.

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“…The frequency of these fast coherence oscillations reflects the large transition energy between the

and

states. High temporal and spectral resolution about CoIn dynamics from jittery, stochastic FEL pulses could also be obtained at the data-processing stage by a correlation analysis ( 19 , 22 ) or machine learning ( 43 ), as recently proposed and investigated experimentally.…”

mentioning

confidence: 99%

Electronic coherences in nonadiabatic molecular photophysics revealed by time-resolved photoelectron spectroscopy

Cavaletto

Keefer

Mukamel

2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Time-resolved photoelectron spectroscopy (TRPES) is a promising technique for the study of ultrafast molecular processes, such as the nonadiabatic dynamics taking place at conical intersections. Directly accessing the evolution of the coherences generated at the conical intersection should provide most valuable dynamical information. However, the signals are dominated by background contributions due to state populations, and most theoretical treatments completely neglect the role of the coherences. Here we show that distinguishable signatures of molecular coherences appear in TRPES. These can be recorded using currently available ultrashort pulses and unambiguously extracted at the postprocessing stage. The technique thus provides direct access to nonadiabatic coherence dynamics.

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Few-fs resolution of a photoactive protein traversing a conical intersection

Cited by 42 publications

References 41 publications

Dynamics retrieval from stochastically weighted incomplete data by low-pass spectral analysis

Dynamics retrieval from stochastically weighted incomplete data by low-pass spectral analysis

Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography

Electronic coherences in nonadiabatic molecular photophysics revealed by time-resolved photoelectron spectroscopy

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