Coupling of retinal, protein, and water dynamics in squid rhodopsin.

The light-induced isomerization of the retinal from 11-cis to all-trans triggers changes in the conformation of visual rhodopsins that lead to the formation of the activated state, which is ready to interact with the G protein. To begin to understand how changes in the structure and dynamics of the retinal are transmitted to the protein, we performed molecular dynamics simulations of squid rhodopsin with 11-cis and all-trans retinal, and with two different force fields for describing the retinal molecule. The results indicate that structural rearrangements in the binding pocket, albeit small, propagate toward the cytoplasmic side of the protein, and affect the dynamics of internal water molecules. The sensitivity of the active-site interactions on the retinal force-field parameters highlights the coupling between the retinal molecule and its immediate protein environment.

[1]  M. Klein,et al.  Constant pressure molecular dynamics algorithms , 1994 .

[2]  Alexander D. MacKerell,et al.  Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties. , 2002, Journal of the American Chemical Society.

[3]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[4]  V. Buss,et al.  Origin and consequences of steric strain in the rhodopsin binding pocket. , 2006, Biochemistry.

[5]  Jeremy C. Smith,et al.  Functional interactions in bacteriorhodopsin: a theoretical analysis of retinal hydrogen bonding with water. , 1995, Biophysical journal.

[6]  M. Elstner,et al.  11-cis-retinal protonated Schiff base: influence of the protein environment on the geometry of the rhodopsin chromophore. , 2002, Biochemistry.

[7]  Krzysztof Palczewski,et al.  Crystal structure of a photoactivated deprotonated intermediate of rhodopsin , 2006, Proceedings of the National Academy of Sciences.

[8]  Klaus Schulten,et al.  Molecular dynamics investigation of primary photoinduced events in the activation of rhodopsin. , 2002, Biophysical journal.

[9]  A. Albert,et al.  Phospholipid fatty acyl spatial distribution in bovine rod outer segment disk membranes. , 1998, Biochimica et biophysica acta.

[10]  Manfred Burghammer,et al.  Structure of bovine rhodopsin in a trigonal crystal form. , 2003, Journal of molecular biology.

[11]  E. Tajkhorshid,et al.  Performance of the AM1, PM3, and SCC-DFTB methods in the study of conjugated Schiff base molecules , 2002 .

[12]  Melvin I. Simon,et al.  Diversity of G proteins in signal transduction , 1991, Science.

[13]  T. Okada,et al.  Crystallographic analysis of primary visual photochemistry. , 2006, Angewandte Chemie.

[14]  Yoshinori Shichida,et al.  Functional role of internal water molecules in rhodopsin revealed by x-ray crystallography , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Sándor Suhai,et al.  Role of Isomerization Barriers in the pKa Control of the Retinal Schiff Base: A Density Functional Study , 1999 .

[16]  Sándor Suhai,et al.  Self-consistent-charge density-functional tight-binding method for simulations of complex materials properties , 1998 .

[17]  Tsutomu Kouyama,et al.  Crystal structure of squid rhodopsin , 2008, Nature.

[18]  Sándor Suhai,et al.  Electronic effects on the ground-state rotational barrier of polyene Schiff bases: A molecular orbital study , 1999 .

[19]  Jeremy C. Smith,et al.  Mechanism of a proton pump analyzed with computer simulations , 2010 .

[20]  Jürgen Hafner,et al.  The Nature of the Complex Counterion of the Chromophore in Rhodopsin , 2004 .

[21]  Sándor Suhai,et al.  The effect of the protein environment on the structure and charge distribution of the retinal Schiff base in bacteriorhodopsin , 1999 .

[22]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[23]  D. Tobias,et al.  Dynamics of the internal water molecules in squid rhodopsin. , 2009, Biophysical journal.

[24]  M. Pitman,et al.  Dynamic structure of retinylidene ligand of rhodopsin probed by molecular simulations. , 2007, Journal of molecular biology.

[25]  Roger Impey,et al.  Hydration and mobility of ions in solution , 1983 .

[26]  B. Brooks,et al.  Constant pressure molecular dynamics simulation: The Langevin piston method , 1995 .

[27]  K. Gawrisch,et al.  Structure and dynamics of polyunsaturated hydrocarbon chains in lipid bilayers-significance for GPCR function. , 2008, Chemistry and physics of lipids.

[28]  Thomas Huber,et al.  Functional role of the "ionic lock"--an interhelical hydrogen-bond network in family A heptahelical receptors. , 2008, Journal of molecular biology.

[29]  H. Khorana,et al.  Location of the Retinal Chromophore in the Activated State of Rhodopsin* , 2009, Journal of Biological Chemistry.

[30]  Alan Grossfield,et al.  Internal hydration increases during activation of the G-protein-coupled receptor rhodopsin. , 2008, Journal of molecular biology.

[31]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[32]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[33]  G. Salgado,et al.  Retinal Conformation and Dynamics in Activation of Rhodopsin Illuminated by Solid‐state 2H NMR Spectroscopy † , 2009, Photochemistry and photobiology.

[34]  G. von Heijne,et al.  Interface connections of a transmembrane voltage sensor. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  V. Buss,et al.  Quantum mechanical studies on the crystallographic model of bathorhodopsin. , 2006, Angewandte Chemie.

[36]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[37]  Marcus Elstner,et al.  The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. , 2004, Journal of molecular biology.

[38]  M. Elstner.  The SCC-DFTB method and its application to biological systems , 2006 .

[39]  T. Mielke,et al.  Electron crystallography reveals the structure of metarhodopsin I , 2004, The EMBO journal.

[40]  Jeremy C. Smith,et al.  Key role of active-site water molecules in bacteriorhodopsin proton-transfer reactions. , 2008, The journal of physical chemistry. B.

[41]  P. Crozier,et al.  How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations , 2006, Proteins.

[42]  M. Karplus,et al.  A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations , 1990 .

[43]  Gerhard Hessler,et al.  Drug Design Strategies for Targeting G‐Protein‐Coupled Receptors , 2002, Chembiochem : a European journal of chemical biology.

[44]  Katrin Sangkuhl,et al.  Mutant G-protein-coupled receptors as a cause of human diseases. , 2004, Pharmacology & therapeutics.

[45]  K Schulten,et al.  Molecular dynamics study of the nature and origin of retinal's twisted structure in bacteriorhodopsin. , 2000, Biophysical journal.

[46]  A. Terakita,et al.  Selective activation of G‐protein subtypes by vertebrate and invertebrate rhodopsins , 1998, FEBS letters.

[47]  H. G. Petersen,et al.  Error estimates on averages of correlated data , 1989 .

[48]  Anthony Watts,et al.  Molecular dynamics simulations of retinal in rhodopsin: from the dark-adapted state towards lumirhodopsin. , 2005, Biochemistry.

[49]  B. Kobilka,et al.  New G-protein-coupled receptor crystal structures: insights and limitations. , 2008, Trends in pharmacological sciences.

[50]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[51]  Michael F. Brown,et al.  Two protonation switches control rhodopsin activation in membranes , 2008, Proceedings of the National Academy of Sciences.

[52]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[53]  Kurt Kristiansen,et al.  Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. , 2004, Pharmacology & therapeutics.

[54]  H. Kandori,et al.  Structural changes in the Schiff base region of squid rhodopsin upon photoisomerization studied by low-temperature FTIR spectroscopy. , 2006, Biochemistry.