Unlocking the Elegance of Molecular ‘Coherence’: Scientists Illuminate the Biological Dance

Utilizing cutting-edge ultrafast physics techniques in the field of structural biology, researchers have illuminated the intricate choreography of molecular “coherence” with unparalleled clarity. This breakthrough sheds light on the behavior of molecules when subjected to stimuli, such as light, a fundamental aspect of biology, as seen in processes like photosynthesis. Scientists have been diligently unraveling these molecular changes in various scientific domains. By merging two of these disciplines, scientists have paved the way for a groundbreaking era in comprehending the reactions of protein molecules, which are indispensable for life itself.

The international research team, under the leadership of Professor Jasper van Thor from the Department of Life Sciences at Imperial, recently published their remarkable discoveries in the prestigious journal Nature Chemistry. In the realm of structural biology, crystallography is a potent tool for capturing “snapshots” of molecular arrangements. Through extensive large-scale experiments and years of theoretical work, the team seamlessly integrated this method with another technique known as spectroscopy, which maps vibrations in the electronic and nuclear configurations of molecules.

Demonstrating their innovative approach at state-of-the-art X-ray laser facilities worldwide, the team unveiled that when optically stimulated, the initial movements of molecules within the studied protein are manifestations of “coherence,” indicating a vibrational effect rather than functional motion in the subsequent biological reaction. This crucial distinction, experimentally demonstrated for the first time, underscores how the physics of spectroscopy can provide fresh insights into the classical crystallography methods used in structural biology.

Professor van Thor elaborated, stating, “Every life-sustaining process relies on proteins, but comprehending the intricacies of how these complex molecules carry out their functions hinges on understanding the arrangement of their atoms and how this structure evolves during reactions. By employing spectroscopic methods, we can now visualize ultrafast molecular motions associated with the so-called coherence process directly through crystal structures. We now possess the tools to fathom and even manipulate molecular dynamics occurring at incredibly swift time scales, with near-atomic precision.”

He further added, “We hope that by sharing the methodological details of this pioneering technique, we can inspire researchers in both the realms of time-resolved structural biology and ultrafast laser spectroscopy to explore the crystallographic aspects of coherence.”

The amalgamation of these techniques necessitated the utilization of X-ray free-electron laser (XFEL) facilities, including the Linac Coherent Light Source (LCLS) in the USA, the SPring-8 Angstrom Compact Free Electron Laser (SACLA) in Japan, the PAL-XFEL in Korea, and more recently, the European XFEL in Hamburg.

Team members have been dedicatedly working at XFELs since 2009 to investigate and comprehend the motions of reacting proteins on the femtosecond timescale, known as femtochemistry. Following excitation by a laser pulse, X-ray snapshots of the structure are captured. While their technique provided an intricate picture of light-induced changes in a biological protein in 2016, a fundamental question remained: What accounts for the minuscule molecular motions occurring in the femtosecond timespan immediately after the initial laser pulse?

Previous research had assumed that all these motions corresponded to the biological reaction, signifying functional motion. However, through their novel approach, the research team determined that this was not the case in their experiments.

To reach this conclusion, they employed “coherent control,” shaping the laser light to manage the protein’s motions predictably. After an initial success at LCLS in Stanford in 2018, validating and refining the method necessitated a total of six experiments at XFEL facilities worldwide, each involving extensive collaboration and large teams.

They then amalgamated the data from these experiments with modified theoretical methods from femtochemistry, enabling them to apply these techniques to X-ray crystallographic data instead of spectroscopic data. The outcome was that the ultrafast motions, measured with remarkable precision on the picometer scale and femtosecond timescale, did not relate to the biological reaction but rather to vibrational coherence in the remaining ground state.

This implies that the motions measured subsequently predominantly pertain to the molecules left behind after the femtosecond laser pulse has passed, albeit only within the so-called vibrational coherence time.

Professor van Thor elucidated, “We concluded that for our experiment, even without incorporating coherent control, the conventional time-resolved measurements were, in fact, dominated by motions originating from the dark ‘reactant’ ground state, which are unrelated to the biological reactions triggered by light. Instead, these motions correspond to what is traditionally observed in vibrational spectroscopy, bearing different yet equally significant implications. This experimental validation aligns with previous theoretical predictions and is poised to have a substantial impact on both time-resolved structural biology and ultrafast spectroscopy. We have now developed and supplied the analytical tools to explore motion on the ultrafast femtosecond timescale.”

This groundbreaking study involved an unprecedented collaboration, with 49 authors from 15 institutions spanning seven years of work, including experiments conducted remotely during the pandemic. Professor van Thor attributed the success of this endeavor to the spirit of cooperation, stating, “In a rapidly evolving field characterized by fierce competition for XFEL beamtime and pressure to publish individual experiments, I am immensely grateful to all co-authors, team members, and collaborators for their persistence, dedication, and commitment to pursuing the broader goal, even if it required a strategic and lengthier approach.”

Co-author Dr. Sébastien Boutet from the SLAC National Accelerator Laboratory expressed, “These results exemplify the unique capabilities of X-ray lasers. They showcase the kind of insights into dynamic biological processes that can only be attained with extremely brief bursts of X-rays, combined with cutting-edge laser technology. We anticipate an exciting future of discoveries in this domain.”

Co-author Professor Gerrit Groenhof from the University of Jyväskylä, Finland, emphasized the significance of coherent control in understanding the molecular dynamics of electronically excited states induced by excitation lasers, particularly in unraveling how photoreceptor proteins have evolved to mediate the photo-activation process. He noted that witnessing such a molecular movie of photobiology in action is not only captivating but may also unlock principles for designing novel light-responsive materials.

[Reference: “Optical control of ultrafast structural dynamics in a fluorescent protein” by Christopher D. M. Hutchison, James M. Baxter, Ann Fitzpatrick, Gabriel Dorlhiac, Alisia Fadini, Samuel Perrett, Karim Maghlaoui, Salomé Bodet Lefèvre, Violeta Cordon-Preciado, Josie L. Ferreira, Volha U. Chukhutsina, Douglas Garratt, Jonathan Barnard, Gediminas Galinis, Flo Glencross, Rhodri M. Morgan, Sian Stockton, Ben Taylor, Letong Yuan, Matthew G. Romei, Chi-Yun Lin, Jon P. Marangos, Marius Schmidt, Viktoria Chatrchyan, Tiago Buckup, Dmitry Morozov, Jaehyun Park, Sehan Park, Intae Eom, Minseok Kim, Dogeun Jang, Hyeongi Choi, HyoJung Hyun, Gisu Park, Eriko Nango, Rie Tanaka, Shigeki Owada, Kensuke Tono, Daniel P. DePonte, Sergio Carbajo, Matt Seaberg, Andrew Aquila, Sebastien Boutet, Anton Barty, So Iwata, Steven

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