Significance
DBP6

Respiration and photosynthesis are ubiquitous bioenergetic processes for harvesting and converting energy in biological cells. Many key proteins and physical processes are common to both processes, featuring organelle-scale arrays of membrane protein complexes. Dysfunction of the repiratory complex is associated with several pathologies, including Parkinson's disease, malaria, and breast cancer. Here, molecular modeling techniques from single-protein to organelle scales are employed to study (1) energy conversion in a respiratory supercomplex, called respirasome, in mitochondria(S1) and (2) energy harvesting by a granal thylakoid membrane in chloroplasts(S2).

Innovation

A central challenge for both (S1) and (S2) is the lack of atomic-detail structural models of the supramolecular organization. The structural model for complex I (NADH dehydrogenase) (S1,S2) as well as the entire respirasome (S1) will be resolved in atomic detail by extending current MDFF methods, driving the development of autoMDFF (TRD3) protocols for the resolution of sub-5 angstrom EM maps. The granal thylakoid (S2), featuring nearly 2 billion atoms and comprising over 10,000 proteins in a 500 nm membrane domain, will be investigated through tools for cell-scale placement of macromolecules (TRD2), large system visualization (TRD2), and the CMMxmasbuilder (TRD3) membrane building protocol for the construction of atomic-detail organelle domains by extending earlier work on bacterial bioenergetic organelles. A further challenge due to the very large system size of S2 is that most experimental laboratories currently lack in-house visualization capabilities for viewing and analyzing systems of this size at atomic detail, whereas the construction of such structural models requires visual data exchange between experimental and computational scientists. This exchange will be facilitated using remote visualization (TRD2) tools employing GPU-clusters in supercomputer centers. A challenge for modeling S1 and S2 is the extensive range of time-scales and length-scales involved in the energy conversion steps, which span from microseconds for proton transport processes to milliseconds for diffusion of redox factors spread over hundreds to thousands of proteins, requiring sampling over many trajectories. The computational demand of such modeling efforts will employ petascale/exascale computing (TRD1) capabilities. Electrostatic potentials based on all-atom structural models will be determined employing the proPka protocols with the advanced electrostatics (TRD2) interface. A related challenge involves pH-dependent kinetics of proton transport in complex I (NADH dehdrogenase) (S1,S2). This transport process will be simulated using constant pH (TRD1) simulations and QM/MM (TRD1) methods. The challenge for modeling the slowest, rate-determining steps involve millisecond scale diffusion processes. Such processes, including electron transfer from complex III/cytochrome b6f onto complex IV (S1) or photosystem I (S2) via carrier proteins cytochrome c/plastocyanin, will be modelled using GPU-BD (TRD3) protocols for atomic resolution Brownian dynamics.

Approach

The investigations described above will be performed based on expertise of the Center over the past four decades on modeling energy conversion processes in bioenergetic systems. Recently, the atomic detailed structure of a bacterial bioenergetic organelle, the photosynthetic chromatophore, was determined based on AFM, cryo-EM, crystallography, and proteomics data (Hunter) and the overall energy conversion into ATP was modeled. Furthermore, a model for the light-harvesting domain of the cyanobacterial thylakoid membrane, containing 96 photosystem I complexes, was also recently constructed based on AFM data (Hunter). Following similar protocols, a granal thylakoid membrane for the plant chloroplast will be constructed for modeling the fundamental energy harvesting processes ({\bf Hunter, Blankenship) (TRD1, TRD2, TRD3). A complete respirasome model will be constructed based on crystallographic and EM data (Sazanov) employing MDFF (TRD3). Key residues predicted during MD simulations of proton transport in complex I and Brownian dynamics simulation of electron transport between complexes III and IV will be confirmed by biochemical data (Gennis) (TRD2, TRD3).

Publications
Publications Database
  • Atomic detail visualization of photosynthetic membranes with GPU-accelerated ray tracing. John E. Stone, Melih Sener, Kirby L. Vandivort, Angela Barragan, Abhishek Singharoy, Ivan Teo, Joao V. Ribeiro, Barry Isralewitz, Bo Liu, Boon Chong Goh, James C. Phillips, Craig MacGregor-Chatwin, Matthew P. Johnson, Lena F. Kourkoutis, C. Neil Hunter, and Klaus Schulten. Parallel Computing, 55:17-27, 2016.
  • Binding site recognition and docking dynamics of a single electron transport protein: Cytochrome c2. Abhishek Singharoy, Angela M. Barragan, Sundarapandian Thangapandian, Emad Tajkhorshid, and Klaus Schulten. Journal of the American Chemical Society, 138:12077-12089, 2016.
  • Overall energy conversion efficiency of a photosynthetic vesicle. Melih Sener, Johan Strümpfer, Abhishek Singharoy, C. Neil Hunter, and Klaus Schulten. eLife, 10.7554/eLife.09541, 2016. (30 pages).
  • Identification of ubiquinol binding motifs at the Qo-site of the cytochrome bc1 complex. Angela M. Barragan, Antony R. Crofts, Klaus Schulten, and Ilia A. Solov'yov. Journal of Physical Chemistry B, 119:433-447, 2015.
  • Light harvesting by lamellar chromatophores in Rhodospirillum photometricum. Danielle Chandler, Johan Strümpfer, Melih Sener, Simon Scheuring, and Klaus Schulten. Biophysical Journal, 106:2503-2510, 2014.
  • Structure, function, and quantum dynamics of pigment-protein complexes. Ioan Kosztin and Klaus Schulten. In Masoud Mohseni, Yasser Omar, Greg Engel, and Martin B. Plenio, editors, Quantum Effects in Biology, pp. 123-143. Cambridge University Press, 2014.
  • Quantum biology of retinal. Shigehiko Hayashi and Klaus Schulten. In Masoud Mohseni, Yasser Omar, Greg Engel, and Martin B. Plenio, editors, Quantum Effects in Biology, pp. 237-263. Cambridge University Press, 2014.
  • On the different types of vibrations interacting with electronic excitations in the PE545 and FMO antenna systems. Mortaza Aghtar, Johann Strümpfer, Carsten Olbrich, Klaus Schulten, and Ulrich Kleinekathoefer. Journal of Physical Chemistry Letters, 5:3131-3137, 2014. (DNA P41).
  • Visualization of energy conversion processes in a light harvesting organelle at atomic detail. Melih Sener, John E. Stone, Angela Barragan, Abhishek Singharoy, Ivan Teo, Kirby L. Vandivort, Barry Isralewitz, Bo Liu, Boon Chong Goh, James C. Phillips, Lena F. Kourkoutis, C. Neil Hunter, and Klaus Schulten. In Proceedings of the International Conference on High Performance Computing, Networking, Storage and Analysis, SC '14. IEEE Press, 2014. (4 pages).
  • Ultrastable cellulosome-adhesion complex tightens under load. Constantin Schoeler, Klara H. Malinowska, Rafael C. Bernardi, Lukas F. Milles, Markus A. Jobst, Ellis Durner, Wolfgang Ott, Daniel B. Fried, Edward A. Bayer, Klaus Schulten, Hermann E. Gaub, and Michael A. Nash. Nature Communications, 5:5635, 2014.
  • Integration of energy and electron transfer processes in the photosynthetic membrane of Rhodobacter sphaeroides. Michaël L. Cartron, John D. Olsen, Melih Sener, Philip J. Jackson, Amanda A. Brindley, Pu Qian, Mark J. Dickman, Graham J. Leggett, Klaus Schulten, and C. Neil Hunter. Biochimica et Biophysica Acta - Bioenergetics, 1837:1769-1780, 2014.
  • The FMO complex in a glycerol-water mixture. Mortaza Aghtar, Johan Strümpfer, Carsten Olbrich, Klaus Schulten, and Ulrich Kleinekathoefer. Journal of Physical Chemistry B, 117:7157-7163, 2013.
  • How quantum coherence assists photosynthetic light harvesting. Johan Strumpfer, Melih Sener, and Klaus Schulten. Journal of Physical Chemistry Letters, 3:536-542, 2012.
  • Vibrationally assisted electron transfer mechanism of olfaction: Myth or reality? Ilia A. Solov'yov, Po-Yao Chang, and Klaus Schulten. Physical Chemistry - Chemical Physics, 14:13861-13871, 2012.
  • Juxtaposing density matrix and classical path-based wave packet dynamics. Mortaza Aghtar, Jörg Liebers, Johan Strümpfer, Klaus Schulten, and Ulrich Kleinekathöfer. Journal of Chemical Physics, 136:214101, 2012. (9 pages).
  • Open quantum dynamics calculations with the hierarchy equations of motion on parallel computers. Johan Strümpfer and Klaus Schulten. Journal of Chemical Theory and Computation, 8:2808-2816, 2012.
  • Decrypting cryptochrome: Revealing the molecular identity of the photoactivation reaction. Ilia A. Solov'yov, Tatiana Domratcheva, Abdul R. M. Shahi, and Klaus Schulten. Journal of the American Chemical Society, 134:18046-18052, 2012.
  • Excited state dynamics in photosynthetic reaction center and light harvesting complex 1. Johan Strümpfer and Klaus Schulten. Journal of Chemical Physics, 137:065101, 2012. (8 pages).
  • Förster energy transfer theory as reflected in the structures of photosynthetic light harvesting systems. Melih Sener, Johan Strümpfer, Jen Hsin, Danielle Chandler, Simon Scheuring, C. Neil Hunter, and Klaus Schulten. ChemPhysChem, 12:518-531, 2011.
  • Photosynthetic vesicle architecture and constraints on efficient energy harvesting. Melih Sener, Johan Strumpfer, John A. Timney, Arvi Freiberg, C. Neil Hunter, and Klaus Schulten. Biophysical Journal, 99:67-75, 2010.
  • Energy transfer dynamics in an RC-LH1-PufX tubular photosynthetic membrane. Jen Hsin, Johan Strümpfer, Melih Sener, Pu Qian, C. Neil Hunter, and Klaus Schulten. New Journal of Physics, 12:085005, 2010. (19 pages).
  • Light harvesting complex II B850 excitation dynamics. Johan Strümpfer and Klaus Schulten. Journal of Chemical Physics, 131:225101, 2009. (9 pages).
  • Molecular dynamics methods for bioelectronic systems in photosynthesis. Ioan Kosztin and Klaus Schulten. In Thijs Aartsma and Joerg Matysik, editors, Biophysical Techniques in Photosynthesis II, volume 26 of Advances in Photosynthesis and Respiration, pp. 445-464. Springer, Dordrecht, 2008.
  • Atomic level structural and functional model of a bacterial photosynthetic membrane vesicle. Melih K. Sener, John D. Olsen, C. Neil Hunter, and Klaus Schulten. Proceedings of the National Academy of Sciences, USA, 104:15723-15728, 2007.
  • Excitation migration in trimeric cyanobacterial photosystem I. Melih K. Sener, Sanghyun Park, Deyu Lu, Ana Damjanovic, Thorsten Ritz, Petra Fromme, and Klaus Schulten. Journal of Chemical Physics, 120:11183-11195, 2004.
  • Calculating potentials of mean force from steered molecular dynamics simulations. Sanghyun Park and Klaus Schulten. Journal of Chemical Physics, 120:5946-5961, 2004.
  • Excitons in a photosynthetic light-harvesting system: A combined molecular dynamics, quantum chemistry and polaron model study. Ana Damjanovic, Ioan Kosztin, Ulrich Kleinekathoefer, and Klaus Schulten. Physical Review E, 65:031919, 2002. (24 pages).
  • A general random matrix approach to account for the effect of static disorder on the spectral properties of light harvesting systems. Melih Sener and Klaus Schulten. Physical Review E, 65:031916, 2002. (12 pages).
  • Robustness and optimality of light harvesting in cyanobacterial photosystem I. Melih K. Sener, Deyu Lu, Thorsten Ritz, Sanghyun Park, Petra Fromme, and Klaus Schulten. Journal of Physical Chemistry B, 106:7948-7960, 2002.
  • Excitons and excitation transfer in the photosynthetic unit of purple bacteria. Thorsten Ritz, Xiche Hu, Ana Damjanovic, and Klaus Schulten. Journal of Luminescence, 76-77:310-321, 1998.
  • The crystal structure of the light harvesting complex II (B800-850) from Rhodospirillum molischianum. Juergen Koepke, Xiche Hu, Cornelia Muenke, Klaus Schulten, and Hartmut Michel. Structure, 4:581-597, 1996.
  • Electron transfer and spin exchange contributing to the magnetic field dependence of the primary photochemical reaction of bacterial photosynthesis. Hans-Joachim Werner, Klaus Schulten, and Albert Weller. Biochimica et Biophysica Acta, 502:255-268, 1978.