Substructured multibody molecular dynamics.

We have enhanced our parallel molecular dynamics (MD) simulation software LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator, lammps.sandia.gov) to include many new features for accelerated simulation including articulated rigid body dynamics via coupling to the Rensselaer Polytechnic Institute code POEMS (Parallelizable Open-source Efficient Multibody Software). We use new features of the LAMMPS software package to investigate rhodopsin photoisomerization, and water model surface tension and capillary waves at the vapor-liquid interface. Finally, we motivate the recipes of MD for practitioners and researchers in numerical analysis and computational mechanics.

[1]  A. Engel,et al.  Atomic-force microscopy: Rhodopsin dimers in native disc membranes , 2003, Nature.

[2]  J. Bowmaker,et al.  The molecular mechanism for the spectral shifts between vertebrate ultraviolet- and violet-sensitive cone visual pigments. , 2002, The Biochemical journal.

[3]  R. Mathies,et al.  Chromophore structure in lumirhodopsin and metarhodopsin I by time-resolved resonance Raman microchip spectroscopy. , 2001, Biochemistry.

[4]  P. Yeagle,et al.  A conformational trigger for activation of a G protein by a G protein-coupled receptor. , 2003, Biochemistry.

[5]  R. Birge,et al.  Vertebrate ultraviolet visual pigments: protonation of the retinylidene Schiff base and a counterion switch during photoactivation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Brown,et al.  Modulation of Rhodopsin Function by Properties of the Membrane Bilayer , 2022 .

[7]  T. Sakmar,et al.  Introduction of hydroxyl-bearing amino acids causes bathochromic spectral shifts in rhodopsin. Amino acid substitutions responsible for red-green color pigment spectral tuning. , 1992, The Journal of biological chemistry.

[8]  S. Larsson,et al.  Primary photoprocess in vision: minimal motion to reach the photo- and bathorhodopsin intermediates. , 2005, The journal of physical chemistry. B.

[9]  V. Arnold.  Mathematical Methods of Classical Mechanics , 1974 .

[10]  T. Sakmar,et al.  pH dependence of photolysis intermediates in the photoactivation of rhodopsin mutant E113Q. , 2000, Biochemistry.

[11]  D. Baylor,et al.  Activation, deactivation, and adaptation in vertebrate photoreceptor cells. , 2001, Annual review of neuroscience.

[12]  T. Sakmar,et al.  Movement of the retinylidene Schiff base counterion in rhodopsin by one helix turn reverses the pH dependence of the metarhodopsin I to metarhodopsin II transition. , 1993, The Journal of biological chemistry.

[13]  H. Khorana,et al.  Glutamic acid-113 serves as the retinylidene Schiff base counterion in bovine rhodopsin. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Clare Ellis,et al.  The state of GPCR research in 2004 , 2004, Nature Reviews Drug Discovery.

[15]  Frank Suits,et al.  Role of cholesterol and polyunsaturated chains in lipid-protein interactions: molecular dynamics simulation of rhodopsin in a realistic membrane environment. , 2005, Journal of the American Chemical Society.

[16]  R. Mathies,et al.  Function of extracellular loop 2 in rhodopsin: glutamic acid 181 modulates stability and absorption wavelength of metarhodopsin II. , 2002, Biochemistry.

[17]  Hans-Dieter Höltje,et al.  Molecular dynamics simulations of bovine rhodopsin: influence of protonation states and different membrane-mimicking environments , 2005, Journal of molecular modeling.

[18]  K. Nakanishi,et al.  Primary events in dim light vision: a chemical and spectroscopic approach toward understanding protein/chromophore interactions in rhodopsin. , 2004, Chemical record.

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

[20]  P. Garriga,et al.  New prospects for drug discovery from structural studies of rhodopsin. , 2005, Current pharmaceutical design.

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

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

[23]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[24]  T. Sakmar,et al.  Rhodopsin activation affects the environment of specific neighboring phospholipids: an FTIR spectroscopic study. , 2000, Biophysical journal.

[25]  R. Birge,et al.  Perspectives on the counterion switch-induced photoactivation of the G protein-coupled receptor rhodopsin , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Kate S. Carroll,et al.  Mechanisms of Spectral Tuning in Blue Cone Visual Pigments , 1998, The Journal of Biological Chemistry.

[27]  Lei Shi,et al.  The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. , 2002, Annual review of pharmacology and toxicology.

[28]  Alexander D. MacKerell,et al.  An Empirical Potential Energy Function for Phospholipids: Criteria for Parameter Optimization and Applications , 1996 .

[29]  R. Hilgenfeld,et al.  Utility of homology models in the drug discovery process , 2004, Drug Discovery Today.

[30]  H. Khorana,et al.  Rhodopsin mutants that bind but fail to activate transducin. , 1990, Science.

[31]  L. Stryer,et al.  Retinal chromophore of rhodopsin photoisomerizes within picoseconds. , 1981, Science.

[32]  Krzysztof Palczewski,et al.  A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface , 2004, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[33]  K. Palczewski,et al.  G protein-coupled receptor rhodopsin: a prospectus. , 2003, Annual review of physiology.

[34]  T. Sakmar,et al.  Time-resolved photointermediate changes in rhodopsin glutamic acid 181 mutants. , 2004, Biochemistry.

[35]  Thomas B Woolf,et al.  Molecular dynamics simulation of dark-adapted rhodopsin in an explicit membrane bilayer: coupling between local retinal and larger scale conformational change. , 2003, Journal of molecular biology.

[36]  K. Fahmy,et al.  Structural determinants of active state conformation of rhodopsin: molecular biophysics approaches. , 2000, Methods in enzymology.

[37]  K. Fahmy,et al.  Regulation of the rhodopsin-transducin interaction by a highly conserved carboxylic acid group. , 1993, Biochemistry.

[38]  Claudio N. Cavasotto,et al.  Structure‐based identification of binding sites, native ligands and potential inhibitors for G‐protein coupled receptors , 2003, Proteins.

[39]  J. Ballesteros,et al.  Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. , 2001, Molecular pharmacology.

[40]  Judith Klein-Seetharaman,et al.  Identification of core amino acids stabilizing rhodopsin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Mathies,et al.  Retinal counterion switch in the photoactivation of the G protein-coupled receptor rhodopsin , 2003, Proceedings of the National Academy of Sciences of the United States of America.

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

[43]  M. Burghammer,et al.  Crystals of native and modified bovine rhodopsins and their heavy atom derivatives. , 2004, Journal of molecular biology.

[44]  A. Dinculescu,et al.  The surface of visual arrestin that binds to rhodopsin. , 2004, Molecular vision.

[45]  S. Larsson,et al.  Initial step of the photoprocess leading to vision only requires minimal atom displacements in the retinal molecule , 2003 .

[46]  R. Mathies,et al.  Structural Observation of the Primary Isomerization in Vision with Femtosecond-Stimulated Raman , 2005, Science.

[47]  Thomas B Woolf,et al.  Discrimination of native loop conformations in membrane proteins: Decoy library design and evaluation of effective energy scoring functions , 2003, Proteins.

[48]  Carlos E. Padilla,et al.  MBO(N)D: A multibody method for long‐time molecular dynamics simulations , 2000 .

[49]  V. Buss,et al.  How the Counterion Affects Ground- and Excited-State Properties of the Rhodopsin Chromophore , 2004 .

[50]  S. O. Smith,et al.  The steric trigger in rhodopsin activation. , 1997, Journal of molecular biology.

[51]  Leslie Greengard,et al.  A fast algorithm for particle simulations , 1987 .

[52]  H. Khorana,et al.  Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin , 1996, Science.

[53]  Krzysztof Palczewski,et al.  Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. , 2003, Biochemistry.

[54]  Marko Schreiber,et al.  Exploring the Opsin shift with ab initio methods: Geometry and counterion effects on the electronic spectrum of retinal. , 2003 .

[55]  Marco Garavelli,et al.  Counterion controlled photoisomerization of retinal chromophore models: a computational investigation. , 2004, Journal of the American Chemical Society.

[56]  K. Fahmy,et al.  A conserved carboxylic acid group mediates light-dependent proton uptake and signaling by rhodopsin. , 1994, The Journal of biological chemistry.

[57]  H Gobind Khorana,et al.  Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. , 2003, Advances in protein chemistry.

[58]  S. O. Smith,et al.  The C9 methyl group of retinal interacts with glycine-121 in rhodopsin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Henklein,et al.  Mutation of the Fourth Cytoplasmic Loop of Rhodopsin Affects Binding of Transducin and Peptides Derived from the Carboxyl-terminal Sequences of Transducin α and γ Subunits* , 2000, The Journal of Biological Chemistry.

[60]  Heidi E. Hamm,et al.  Structural determinants for activation of the α-subunit of a heterotrimeric G protein , 1994, Nature.

[61]  T. Sakmar,et al.  The Effects of Amino Acid Replacements of Glycine 121 on Transmembrane Helix 3 of Rhodopsin* , 1996, The Journal of Biological Chemistry.

[62]  K. Anderson.  An order n formulation for the motion simulation of general multi-rigid-body constrained systems , 1992 .

[63]  John S. Rowlinson,et al.  Molecular Theory of Capillarity , 1983 .

[64]  C. Tanford.  Macromolecules , 1994, Nature.

[65]  T. Huber,et al.  Membrane model for the G-protein-coupled receptor rhodopsin: hydrophobic interface and dynamical structure. , 2004, Biophysical journal.

[66]  J. Stoer,et al.  Introduction to Numerical Analysis , 2002 .

[67]  T. Sakmar,et al.  Evidence for the specific interaction of a lipid molecule with rhodopsin which is altered in the transition to the active state metarhodopsin II 1 , 1998, FEBS letters.

[68]  T. Okada.  X-ray crystallographic studies for ligand-protein interaction changes in rhodopsin. , 2004, Biochemical Society transactions.

[69]  H. Khorana,et al.  The role of the retinylidene Schiff base counterion in rhodopsin in determining wavelength absorbance and Schiff base pKa. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[70]  T. Sakmar,et al.  Rhodopsin: insights from recent structural studies. , 2002, Annual review of biophysics and biomolecular structure.

[71]  T. Sakmar,et al.  The Amino Terminus of the Fourth Cytoplasmic Loop of Rhodopsin Modulates Rhodopsin-Transducin Interaction* , 2000, The Journal of Biological Chemistry.

[72]  Karen Sparck Jones,et al.  The Key Concepts , 2004 .

[73]  Burton J. Litman,et al.  Optimization of Receptor-G Protein Coupling by Bilayer Lipid Composition I , 2001, The Journal of Biological Chemistry.

[74]  Jeremy C. Smith,et al.  Ab initio quantum chemical analysis of Schiff base-water interactions in bacteriorhodopsin , 1993 .

[75]  S. Feller,et al.  Rhodopsin exhibits a preference for solvation by polyunsaturated docosohexaenoic acid. , 2003, Journal of the American Chemical Society.

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

[77]  J. Mollon,et al.  Molecular evolution of trichromacy in primates , 1998, Vision Research.

[78]  S. O. Smith,et al.  Role of the C9 methyl group in rhodopsin activation: characterization of mutant opsins with the artificial chromophore 11-cis-9-demethylretinal. , 1998, Biochemistry.

[79]  A. Watts,et al.  The ring of the rhodopsin chromophore in a hydrophobic activation switch within the binding pocket. , 2004, Journal of molecular biology.

[80]  G. Marshall,et al.  Modeling flexible loops in the dark-adapted and activated states of rhodopsin, a prototypical G-protein-coupled receptor. , 2005, Biophysical journal.

[81]  A. Terakita,et al.  Conserved proline residue at position 189 in cone visual pigments as a determinant of molecular properties different from rhodopsins. , 2002, Biochemistry.

[82]  H. Khorana,et al.  A single amino acid substitution in rhodopsin (lysine 248----leucine) prevents activation of transducin. , 1988, The Journal of biological chemistry.

[83]  K. Nakanishi,et al.  Movement of retinal along the visual transduction path. , 2000, Science.

[84]  J. Munkres,et al.  Calculus on Manifolds , 1965 .

[85]  Jonathan A Javitch,et al.  The Ants Go Marching Two by Two: Oligomeric Structure of G-Protein-Coupled Receptors , 2004, Molecular Pharmacology.

[86]  S. Larsson,et al.  Using 1,3-butadiene and 1,3,5-hexatriene to model the cis-trans isomerization of retinal, the chromophore in the visual pigment rhodopsin , 2002 .

[87]  S. A. Hassan,et al.  Key issues in the computational simulation of GPCR function: representation of loop domains , 2002, J. Comput. Aided Mol. Des..

[88]  A. Hirshfeld,et al.  Agonists and partial agonists of rhodopsin: retinals with ring modifications. , 2005, Biochemistry.

[89]  K. Fahmy,et al.  Identification of glutamic acid 113 as the Schiff base proton acceptor in the metarhodopsin II photointermediate of rhodopsin. , 1994, Biochemistry.

[90]  Shay Bar-Haim,et al.  G protein-coupled receptors: in silico drug discovery in 3D. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  T. Sakmar,et al.  The Function of Interdomain Interactions in Controlling Nucleotide Exchange Rates in Transducin* , 2001, The Journal of Biological Chemistry.

[92]  H. Khorana,et al.  Structure and function in rhodopsin. Studies of the interaction between the rhodopsin cytoplasmic domain and transducin. , 1992, The Journal of biological chemistry.

[93]  K. Palczewski,et al.  Isomerization of all-trans-9- and 13-desmethylretinol by retinal pigment epithelial cells. , 1999, Biochemistry.

[94]  T. Sakmar,et al.  Functional Interaction of Transmembrane Helices 3 and 6 in Rhodopsin , 1996, The Journal of Biological Chemistry.

[95]  Masakatsu Watanabe,et al.  Dynamics of molecules with internal degrees of freedom by multiple time-step methods , 1993 .

[96]  D. Farrens,et al.  Role of the Retinal Hydrogen Bond Network in Rhodopsin Schiff Base Stability and Hydrolysis* , 2004, Journal of Biological Chemistry.

[97]  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.

[98]  M. Tuckerman,et al.  Understanding Modern Molecular Dynamics: Techniques and Applications , 2000 .

[99]  D C Teller,et al.  Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). , 2001, Biochemistry.

[100]  A. Hirshfeld,et al.  Coupling of retinal isomerization to the activation of rhodopsin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[101]  Mauricio Carrillo-Tripp,et al.  Evidence for a mechanism by which omega-3 polyunsaturated lipids may affect membrane protein function. , 2005, Biochemistry.

[102]  Krzysztof Palczewski,et al.  The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors. , 2003, Annual review of biophysics and biomolecular structure.

[103]  T. Sakmar,et al.  Characterization of Rhodopsin Mutants That Bind Transducin but Fail to Induce GTP Nucleotide Uptake , 1995, The Journal of Biological Chemistry.

[104]  K. Palczewski,et al.  Activation of rhodopsin: new insights from structural and biochemical studies. , 2001, Trends in biochemical sciences.

[105]  D. Oprian,et al.  Role of the 9-methyl group of retinal in cone visual pigments. , 2004, Biochemistry.

[106]  S. M. Ulam,et al.  Measure-Preserving Homeomorphisms and Metrical Transitivity , 1941 .

[107]  T. Lamb,et al.  Dark adaptation and the retinoid cycle of vision , 2004, Progress in Retinal and Eye Research.

[108]  L. Reichl.  A modern course in statistical physics , 1980 .

[109]  Steffen Lüdeke,et al.  The role of Glu181 in the photoactivation of rhodopsin. , 2005, Journal of molecular biology.

[110]  T. Sakmar,et al.  Characterization of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Mutations on the cytoplasmic surface affect transducin activation. , 1993, The Journal of biological chemistry.

[111]  Ursula Rothlisberger,et al.  Solvent and protein effects on the structure and dynamics of the rhodopsin chromophore. , 2005, Chemphyschem : a European journal of chemical physics and physical chemistry.

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

[113]  D. C. Mitchell,et al.  Optimization of Receptor-G Protein Coupling by Bilayer Lipid Composition I , 2001, The Journal of Biological Chemistry.

[114]  Duan Yang,et al.  The evolution of transmembrane helix kinks and the structural diversity of G protein-coupled receptors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[115]  D C Teller,et al.  Crystal structure of rhodopsin: a template for cone visual pigments and other G protein-coupled receptors. , 2002, Biochimica et biophysica acta.

[116]  K. Fahmy,et al.  Characterization of rhodopsin-transducin interaction: a mutant rhodopsin photoproduct with a protonated Schiff base activates transducin. , 1994, Biochemistry.

[117]  G. Salgado,et al.  Deuterium NMR structure of retinal in the ground state of rhodopsin. , 2004, Biochemistry.

[118]  F. Jelezko,et al.  Membrane Environment Reduces the Accessible Conformational Space Available to an Integral Membrane Protein , 2003 .

[119]  D. Farrens,et al.  Assessing structural elements that influence Schiff base stability: mutants E113Q and D190N destabilize rhodopsin through different mechanisms , 2003, Vision Research.

[120]  S. O. Smith,et al.  Constitutive activation of opsin by mutation of methionine 257 on transmembrane helix 6. , 1998, Biochemistry.

[121]  K. Palczewski,et al.  Crystal structure of rhodopsin: implications for vision and beyond. , 2001, Current opinion in structural biology.

[122]  M. Wheatley,et al.  The third extracellular loop of G-protein-coupled receptors: more than just a linker between two important transmembrane helices. , 2004, Biochemical Society transactions.

[123]  G Vriend,et al.  Heavier‐than‐air flying machines are impossible , 2004, FEBS letters.

[124]  R W Hockney,et al.  Computer Simulation Using Particles , 1966 .

[125]  S. Yokoyama.  Molecular evolution of color vision in vertebrates. , 2002, Gene.

[126]  T. Sakmar,et al.  Spectroscopic evidence for interaction between transmembrane helices 3 and 5 in rhodopsin. , 1998, Biochemistry.

[127]  D. C. Mitchell,et al.  DHA-rich phospholipids optimize G-Protein-coupled signaling. , 2003, The Journal of pediatrics.

[128]  T. Sakmar.  Rhodopsin: a prototypical G protein-coupled receptor. , 1998, Progress in nucleic acid research and molecular biology.

[129]  G. Kochendoerfer,et al.  How color visual pigments are tuned. , 1999, Trends in biochemical sciences.

[130]  H. Khorana,et al.  Total synthesis of a gene for bovine rhodopsin. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[131]  P. Robinson,et al.  Experimental and computational studies of the desensitization process in the bovine rhodopsin-arrestin complex. , 2004, Biophysical journal.

[132]  H Gobind Khorana,et al.  Structural origins of constitutive activation in rhodopsin: Role of the K296/E113 salt bridge. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[133]  Yael Marantz,et al.  Modeling the 3D structure of GPCRs: advances and application to drug discovery. , 2003, Current opinion in drug discovery & development.

[134]  V. Gurevich,et al.  The interaction with the cytoplasmic loops of rhodopsin plays a crucial role in arrestin activation and binding , 2003, Journal of neurochemistry.

[135]  N. G. Abdulaev.  Building a stage for interhelical play in rhodopsin. , 2003, Trends in biochemical sciences.

[136]  T. Sakmar,et al.  Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same. , 2002, Current opinion in cell biology.

[137]  K. Hofmann,et al.  Transition of Rhodopsin into the Active Metarhodopsin II State Opens a New Light-induced Pathway Linked to Schiff Base Isomerization* , 2004, Journal of Biological Chemistry.

[138]  K. Fahmy,et al.  A mutant rhodopsin photoproduct with a protonated Schiff base displays an active-state conformation: a Fourier-transform infrared spectroscopy study. , 1994, Biochemistry.

[139]  F. Bernardi,et al.  The retinal chromophore/chloride ion pair: structure of the photoisomerization path and interplay of charge transfer and covalent states. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[140]  L. Stryer,et al.  Photolyzed rhodopsin catalyzes the exchange of GTP for bound GDP in retinal rod outer segments. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[141]  D. C. Mitchell,et al.  Enhancement of G protein-coupled signaling by DHA phospholipids , 2003, Lipids.

[142]  D. C. Mitchell,et al.  The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways , 2001, Journal of Molecular Neuroscience.

[143]  M. Ishiguro,et al.  Constraints of Opsin Structure on the Ligand‐binding Site: Studies with Ring‐fused Retinals ¶ , 2002, Photochemistry and photobiology.

[144]  K. Fahmy,et al.  Protonation states of membrane-embedded carboxylic acid groups in rhodopsin and metarhodopsin II: a Fourier-transform infrared spectroscopy study of site-directed mutants. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[145]  Robert S. H. Liu,et al.  The molecular basis for the high photosensitivity of rhodopsin , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[146]  J. M. Haile,et al.  Molecular dynamics simulation : elementary methods / J.M. Haile , 1992 .

[147]  Weingart,et al.  Fast Photoisomerization of a Rhodopsin Model-An Ab Initio Molecular Dynamics Study This work was supported by the Deutsche Forschungsgemeinschaft (Graduate College "Struktur und Dynamikheterogener Systeme"). , 2000, Angewandte Chemie.

[148]  E. Hairer,et al.  Geometric Numerical Integration: Structure Preserving Algorithms for Ordinary Differential Equations , 2004 .

[149]  James Critchley,et al.  POEMS: parallelizable open-source efficient multibody software , 2006, Engineering with Computers.

[150]  O. Lichtarge,et al.  Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F , 1996, Nature.

[151]  Mark E. Tuckerman,et al.  Molecular dynamics in systems with multiple time scales: Systems with stiff and soft degrees of freedom and with short and long range forces , 1991 .

[152]  Caterina Bissantz,et al.  Conformational Changes of G Protein‐Coupled Receptors During Their Activation by Agonist Binding , 2003, Journal of receptor and signal transduction research.

[153]  Mirko Krpan,et al.  Dynamics - Theory and application , 2001 .

[154]  Alessandro Laio,et al.  A molecular spring for vision. , 2004, Journal of the American Chemical Society.

[155]  Arthur Christopoulos,et al.  Allosteric modulation of G protein-coupled receptors. , 2007, Annual review of pharmacology and toxicology.