Abstract:
:We present a hybrid computational methodology to predict multiple energetically accessible conformations for G protein-coupled receptors (GPCRs) that might play a role in binding to ligands and different signaling partners. To our knowledge, this method, termed ActiveGEnSeMBLE, enables the first quantitative energy profile for GPCR activation that is consistent with the qualitative profile deduced from experiments. ActiveGEnSeMBLE starts with a systematic coarse grid sampling of helix tilts/rotations (∼13 trillion transmembrane-domain conformations) and selects the conformational landscape based on energy. This profile identifies multiple potential active-state energy wells, with the TM3-TM6 intracellular distance as an approximate activation coordinate. These energy wells are then sampled locally using a finer grid to find locally minimized conformation in each energy well. We validate this strategy using the inactive and active experimental structures of β2 adrenergic receptor (hβ2AR) and M2 muscarinic acetylcholine receptor. Structures of membrane-embedded hβ2AR along its activation coordinate are subjected to molecular-dynamics simulations for relaxation and interaction energy analysis to generate a quantitative energy landscape for hβ2AR activation. This landscape reveals several metastable states along this coordinate, indicating that for hβ2AR, the agonist alone is not enough to stabilize the active state and that the G protein is necessary, consistent with experimental observations. The method's application to somatostatin receptor SSTR5 (no experimental structure available) shows that to predict an active conformation it is better to start from an inactive structure template based on a close homolog than to start from an active template based on a distant homolog. The energy landscape for hSSTR5 activation is consistent with hβ2AR in the role of the G protein. These results demonstrate the utility of the ActiveGEnSeMBLE method for predicting multiple conformations along the pathways for activating GPCRs and the corresponding energy landscapes, thereby providing detailed structural insights into the initial molecular events of GPCR function that are not easily accessible by experiments.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Dong SS,Goddard WA 3rd,Abrol Rdoi
10.1016/j.bpj.2016.04.028subject
Has Abstractpub_date
2016-06-21 00:00:00pages
2618-2629issue
12eissn
0006-3495issn
1542-0086pii
S0006-3495(16)30231-4journal_volume
110pub_type
杂志文章abstract::The diffusion of plastoquinol and its binding to the cytochrome bf complex, which occurs during linear photosynthetic electron transport and is analogous to reaction sequences found in most energy-converting membranes, has been studied in intact thylakoid membranes. The flash-induced electron transfer between the late...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(90)82445-0
更新日期:1990-10-01 00:00:00
abstract::Experimentally, short peptides have been shown to form amyloids similar to those of their parent proteins. Consequently, they present useful systems for studies of amyloid conformation. Here we simulate extensively the NFGAIL peptide, derived from the human islet amyloid polypeptide (residues 22-27). We simulate diffe...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(03)74996-0
更新日期:2003-03-01 00:00:00
abstract::We present a qualitative computer graphics approach to the characterization of forces important to the assembly of beta domains that should have general utility for examining protein interactions and assembly. In our approach, the nature of the molecular surface buried by the domain contacts, the specificity of the re...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(86)83634-7
更新日期:1986-01-01 00:00:00
abstract::Crawling cells have characteristic shapes that are a function of their cell types. How their different shapes are determined is an interesting question. Fish epithelial keratocytes are an ideal material for investigating cell shape determination, because they maintain a nearly constant fan shape during their crawling ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.12.014
更新日期:2016-01-19 00:00:00
abstract::We present a detailed motion analysis of retrograde nerve growth factor (NGF) endosomes in axons to show that mechanical tugs-of-war and intracellular motor regulation are complimentary features of the near-unidirectional endosome directionality. We used quantum dots to fluorescently label NGF and acquired trajectorie...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.04.036
更新日期:2015-06-02 00:00:00
abstract::The domains of the giant muscle protein titin (connectin) provide interaction sites for other sarcomeric proteins and fulfill mechanical functions. In this paper we compare the unfolding forces of defined regions of different titin isoforms by single-molecule force spectroscopy. Constructs comprising six to eight immu...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(98)77741-0
更新日期:1998-12-01 00:00:00
abstract::Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.106.090183
更新日期:2007-06-15 00:00:00
abstract::The properties of phosphatidylcholines (PCs) having a perdeuterated stearic acid, 18:0d35, in the sn-1 position and the fatty acid 18:0, 18:1 omega 9, 18:2 omega 6, 18:3 omega 3, 20:4 omega 6, 20:5 omega 3, or 22:6 omega 3 at the sn-2 position were investigated in a matrix of dioleoylphosphatidylethanolamine (DOPE) by...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(96)79223-8
更新日期:1996-07-01 00:00:00
abstract::The mathematics of the binomial model for quantal neurotransmitter release is considered in general terms, to explore what information might be extractable from statistical aspects of data. For an array of N statistically independent release sites, each with a release probability p, the compound binomial always pertai...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/s0006-3495(97)78709-5
更新日期:1997-02-01 00:00:00
abstract::A combined experimental and theoretical study is performed on binary dilauroylphosphatidylcholine/distearoylphosphatidylcholine (DLPC/DSPC) lipid bilayer membranes incorporating bacteriorhodopsin (BR). The system is designed to investigate the possibility that BR, via a hydrophobic matching principle related to the di...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(97)78225-0
更新日期:1997-10-01 00:00:00
abstract::The effects of Hofmeister anions on the perpendicular and lateral equation-of-state (EOS) of the dipalmitoylphosphatidylcholine lamellar phase discussed in the companion article are here examined using appropriate free energy models for the intra- and interbilayer interactions. Minimizing the free energy with respect ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.107.109264
更新日期:2007-09-01 00:00:00
abstract::Actomyosin interactions were examined by using yeast actin mutants with alanines replacing charged amino acid pairs D24/D25, E99/E100, D80/D81, and E83/K84. In the in vitro motility experiments, actin filaments of D24A/D25A or E99A/E100A mutants moved in the presence of 0.7% methylcellulose at the velocities of wild-t...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::Five molecular dynamics computer simulations were performed on different phospholipid:sterol membrane systems in order to study the influence of sterol structure on membrane properties. Three of these simulated bilayer systems were composed of a 1:8 sterol:phospholipid ratio, each of which employed one of the sterol m...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(01)76137-1
更新日期:2001-04-01 00:00:00
abstract::The structural basis of the wide variability of the physical properties of fibrin clots and the process of assembly of the clot were investigated by electron microscopy of fibers formed under various ionic conditions. In addition, highly specific proteolytic enzymes from different snake venoms were used to remove sele...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(86)83552-4
更新日期:1986-12-01 00:00:00
abstract::Diffusion of the chloride salts of Li, Na, K, Rb, and Cs from water into 1-butanol and from 1-butanol into water was examined at temperatures from 13-40 degrees C. Distribution coefficients, interfacial transfer coefficients, Arrhenius activation energy, free energy of activation, enthalpy, and entropy of activation w...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(66)86697-3
更新日期:1966-11-01 00:00:00
abstract::The effects of lysolipids on phospholipid layer curvature and bending elasticity were examined using x-ray diffraction and the osmotic stress method. Lysolipids with two different head groups, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and differing hydrocarbon chains were mixed with the hexagonal-for...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(01)75695-0
更新日期:2001-07-01 00:00:00
abstract::Magic-angle spinning nuclear magnetic resonance is well suited for the study of membrane proteins in the nativelike lipid environment. However, the natural cellular membrane is invariably more complex than the proteoliposomes most often used for solid-state NMR (SSNMR) studies, and differences may affect the structure...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.02.018
更新日期:2015-04-07 00:00:00
abstract::We present MEMLET (MATLAB-enabled maximum-likelihood estimation tool), a simple-to-use and powerful program for utilizing maximum-likelihood estimation (MLE) for parameter estimation from data produced by single-molecule and other biophysical experiments. The program is written in MATLAB and includes a graphical user ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2016.06.019
更新日期:2016-07-26 00:00:00
abstract::During protein synthesis dictated by the codon sequence of messenger RNA, the ribosome selects aminoacyl-tRNA (aa-tRNA) with high accuracy, the exact mechanism of which remains elusive. By using a single-molecule fluorescence resonance energy transfer method coupled with fluorescence emission anisotropy, we provide ev...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2010.10.026
更新日期:2010-12-01 00:00:00
abstract::It is now known that the flexibility of the troponin T (TnT) tail determines thin filament conformation and hence cross-bridge cycling properties, expanding the classic structural role of TnT to a dynamic role regulating sarcomere function. Here, using transgenic mice bearing R-92W and R-92L missense mutations in card...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.107.107557
更新日期:2007-09-01 00:00:00
abstract::The published reports of flash-induced absorbance changes in the 680-690 nm spectral region, which have been attributed to bleaching of the primary reaction center chlorophyll of photosystem II (PSII) P-680, are discussed in light of what is known about the primary electron acceptor of PSII, C-550. The question of whe...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(72)86128-9
更新日期:1972-07-01 00:00:00
abstract::We perform single-molecule spatial tracking measurements of a DNA repair protein, the C-terminal domain of Ada (C-Ada) from Escherichia coli, moving on DNA extended by flow. The trajectories of single proteins labeled with a fluorophore are constructed. We analyze single-protein dwell times on DNA for different flow r...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2008.11.021
更新日期:2009-03-04 00:00:00
abstract::The classical cable equation, in which membrane conductance is considered constant, is modified by including the linearized effect of membrane potential on sodium and potassium ionic currents, as formulated in the Hodgkin-Huxley equations for the squid giant axon. The resulting partial differential equation is solved ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(69)86446-5
更新日期:1969-10-01 00:00:00
abstract::Cell-reorganized fibronectin layers on polymer films providing a gradation of the binding strength between protein and substrate were analyzed by combined fluorescence and scanning force microscopy. The nanoscale fibronectin patterns exhibited paired parallel fibrils with characteristic spacings of 156, 233, 304, and ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.104.048074
更新日期:2005-01-01 00:00:00
abstract::Nonlinear optical Stokes ellipsometric (NOSE) microscopy was demonstrated for the analysis of collagen-rich biological tissues. NOSE is based on polarization-dependent second harmonic generation imaging. NOSE was used to access the molecular-level distribution of collagen fibril orientation relative to the local fiber...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2016.05.055
更新日期:2016-10-04 00:00:00
abstract::The cell membrane of Salinibacter ruber contains xanthorhodopsin, a light-driven transmembrane proton pump with two chromophores: a retinal and the carotenoid, salinixanthin. Action spectra for transport had indicated that light absorbed by either is utilized for function. If the carotenoid is an antenna in this prote...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.108.132175
更新日期:2008-09-01 00:00:00
abstract::The crystal structure and a 96-ps molecular dynamics simulation used to analyze structural and motional contributions to spin-lattice (T1) relaxation times of phenylalanine and tyrosine C gamma carbons of the pancreatic trypsin inhibitor. The H beta and H delta protons geminal to C gamma are calculated to account for ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(82)84496-2
更新日期:1982-07-01 00:00:00
abstract::EXACT FORMULAS ARE DERIVED FOR THE ENERGY CHANGE OF A DIPOLE SYSTEM WITH TWO ENERGY STATES (OR BANDS) IN A CHANGING FIELD IN TWO CASES: (a) no dipole flip-flop and (b) dipole flip-flop caused by stimulation. Based on these formulas, the positive and negative heats are calculated. The results are in good agreement with...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(72)86152-6
更新日期:1972-09-01 00:00:00
abstract::The mechanisms that limit the speed at which striated muscles relax are poorly understood. This work presents, to our knowledge, novel simulations that show that the time course of relaxation is accelerated by interfilamentary movement resulting from series compliance; force drops faster when myosin heads move relativ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.12.024
更新日期:2016-02-02 00:00:00
abstract::Coupled folding-binding is central to the function of many intrinsically disordered proteins, yet not fully understood. With a continuous three-letter protein model, we explore the free-energy landscape of pairs of interacting sequences and how it is impacted by 1), variations in the binding mechanism; and 2), the add...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2011.12.008
更新日期:2012-02-08 00:00:00