Frontiers in Multiscale Modelling of Photoreceptor Proteins

September 3, 2019 to September 5, 2019
Location : CECAM-ISR


  • Igor Schapiro (The Hebrew University of Jerusalem, Israel)
  • Maria Andrea Mroginski (Technical University of Berlin, Germany)


  • Yael Yogev (Tel Aviv University, Israel)
  • Supports


    SFB 1078

    Fritz Haber Center for Molecular Dynamics Research


    A. Introduction and Motivation
    Photoreceptor proteins are the key molecules for response to and sensing of light in many organisms.1 They mediate a variety of functions in nature such as visual perception, regulation of circadian rhythm, phototaxis and light-oriented growth of plants. Typically, photoreceptor proteins consist of a protein moiety and an embedded chromophore, which is responsible for light absorption at a specific wavelength. Upon illumination, the light absorbed by the chromophore is efficiently converted into molecular energy. This initiates a cascade of biochemical reactions that eventually lead to signal transduction and a physiological response of a cell or of an entire organism. Hence, these proteins represent signal converters that translate light into biological information.2 This energy conversion is increasingly utilized in a wide range of biotechnological applications. For instance: in optogenetics photoreceptors are used to selectively control and monitor neuronal activity.3 This method has already yielded important insights into human problems, including depression, disordered sleep, Parkinson’s disease and schizophrenia. However, in order to exploit the full potential of photoreceptor proteins a detailed molecular level understanding is required. Such a comprehensive understanding can be derived from multiscale simulations.

    B. State of the Art
    In order to model photoreceptor proteins the combined or hybrid quantum-mechanics/molecular mechanics (QM/MM) scheme is the method of choice.4,5 This multiscale method makes the calculations of large protein-chromophore complexes feasible by treating the chemically active region quantum-mechanically (QM) while describing the protein with efficient force-field-based molecular mechanics (MM). The key steps in setting up the QM/MM simulation involves the partitioning in the QM and MM systems and the choice of suitable methods.
    Successful applications of the QM/MM method were recently reported for different families of photoreceptor proteins: retinal proteins,6-9 green fluorescent proteins,10,11 photoactive yellow protein,12,13 phytochromes and flavin binding proteins (cryptochromes14 and BLUF domain15,16).

    C. Objectives
    The idea behind the proposed workshop is bring together leading experts in the field of multiscale simulation of photoreceptor proteins and the corresponding method development. The unifying theme is the derivation of a detailed understanding of the light-induced processes in these proteins. The invited experts work on different photoreceptor protein families but also on different methodologies in this research. Specific questions and challenges are grouped by two main subjects in the photoreceptor protein research:
    1) Spectral Tuning describes the effect of the protein environment on the chromophore’s absorption.17-19 The following advances will be discussed:
    a. What is the effect of the polarizable force field?
    b. What is the optimal strategy to sample the geometries?
    c. How to partition the protein in a QM and MM region?
    2) Excited state reactivity in photoreceptor proteins will encompass different type of reaction, e.g. photoisomerization, excited state proton transfer.20,21
    a. Which approximation can be used for nonadiabatic dynamics?
    b. How can intersystem crossings be calculated?
    c. What is the role of quantum nuclear effects?

    A half-day session will be dedicated for each of the six intriguing questions raised above. Hence, this workshop will bring together scientists who belong to different communities. This unique compilation is expected to facilitate interaction across disciplines and will foster synergetic collaborations that will help to advance the field of photoreceptor proteins.



    1 Heintzen, C. Plant and fungal photopigments. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1, 411-432, doi:10.1002/wmts.36 (2012).
    2 Kennis, J. T. M. & Mathes, T. Molecular eyes: proteins that transform light into biological information. Interface Focus 3, doi:10.1098/rsfs.2013.0005 (2013).
    3 Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience 8, 1263, doi:10.1038/nn1525 (2005).
    4 Senn, H. M. & Thiel, W. QM/MM Methods for Biomolecular Systems. Angewandte Chemie International Edition 48, 1198-1229, doi:10.1002/anie.200802019 (2009).
    5 Warshel, A. & Levitt, M. Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. Journal of Molecular Biology 103, 227-249, doi: (1976).
    6 Schnedermann, C. et al. Evidence for a vibrational phase-dependent isotope effect on the photochemistry of vision. Nature Chemistry 10, 449-455, doi:10.1038/s41557-018-0014-y (2018).
    7 Kamiya, M. & Hayashi, S. Photoactivation Intermediates of a G-Protein Coupled Receptor Rhodopsin Investigated by a Hybrid Molecular Simulation. The Journal of Physical Chemistry B 121, 3842-3852, doi:10.1021/acs.jpcb.6b13050 (2017).
    8 Strambi, A., Durbeej, B., Ferré, N. & Olivucci, M. Anabaena sensory rhodopsin is a light-driven unidirectional rotor. Proceedings of the National Academy of Sciences 107, 21322 (2010).
    9 Suomivuori, C.-M., Gamiz-Hernandez, A. P., Sundholm, D. & Kaila, V. R. I. Energetics and dynamics of a light-driven sodium-pumping rhodopsin. Proceedings of the National Academy of Sciences 114, 7043 (2017).
    10 Park, J. W. & Rhee, Y. M. Electric Field Keeps Chromophore Planar and Produces High Yield Fluorescence in Green Fluorescent Protein. Journal of the American Chemical Society 138, 13619-13629, doi:10.1021/jacs.6b06833 (2016).
    11 Grigorenko, B. L., Krylov, A. I. & Nemukhin, A. V. Molecular Modeling Clarifies the Mechanism of Chromophore Maturation in the Green Fluorescent Protein. Journal of the American Chemical Society 139, 10239-10249, doi:10.1021/jacs.7b00676 (2017).
    12 Pande, K. et al. Femtosecond structural dynamics drives the trans/cis isomerization in photoactive yellow protein. Science 352, 725-729 (2016).
    13 Both, J. H., Parrish, R. M., Martínez, T. J. & Boxer, S. G. Rational Protein Design via Structure-Energetics-Function Relationships in the Photoactive Yellow Protein (PYP) Model System. Biophysical Journal 114, 410a, doi: (2018).
    14 Solov'yov, I. A., Domratcheva, T. & Schulten, K. Separation of photo-induced radical pair in cryptochrome to a functionally critical distance. Scientific Reports 4, 3845, doi:10.1038/srep03845 (2014).
    15 Domratcheva, T., Hartmann, E., Schlichting, I. & Kottke, T. Evidence for Tautomerisation of Glutamine in BLUF Blue Light Receptors by Vibrational Spectroscopy and Computational Chemistry. Scientific Reports 6, 22669, doi:10.1038/srep22669 (2016).
    16 Goyal, P. & Hammes-Schiffer, S. Role of active site conformational changes in photocycle activation of the AppA BLUF photoreceptor. Proceedings of the National Academy of Sciences 114, 1480 (2017).
    17 Hoffmann, M. et al. Color Tuning in Rhodopsins:  The Mechanism for the Spectral Shift between Bacteriorhodopsin and Sensory Rhodopsin II. Journal of the American Chemical Society 128, 10808-10818, doi:10.1021/ja062082i (2006).
    18 Loco, D., Buda, F., Lugtenburg, J. & Mennucci, B. The Dynamic Origin of Color Tuning in Proteins Revealed by a Carotenoid Pigment. The Journal of Physical Chemistry Letters 9, 2404-2410, doi:10.1021/acs.jpclett.8b00763 (2018).
    19 Campomanes, P. et al. Origin of the Spectral Shifts among the Early Intermediates of the Rhodopsin Photocycle. Journal of the American Chemical Society 136, 3842-3851, doi:10.1021/ja411303v (2014).
    20 Ben-Nun, M., Quenneville, J. & Martínez, T. J. Ab Initio Multiple Spawning:  Photochemistry from First Principles Quantum Molecular Dynamics. The Journal of Physical Chemistry A 104, 5161-5175, doi:10.1021/jp994174i (2000).
    21 Bediako, D. K. et al. Role of pendant proton relays and proton-coupled electron transfer on the hydrogen evolution reaction by nickel hangman porphyrins. Proceedings of the National Academy of Sciences 111, 15001 (2014).