499 research outputs found
A hierarchical approach to the prediction of the quaternary structure of GCN4 and its mutants
First published in DIMACS Series in Discrete Mathematics and Theoretical Computer Science, 23 (1996) published by the American Mathematical Society.Presented at DIMACS Workshop on Global Minimization of Nonconvex Energy Functions: Molecular Conformation and Protein Folding, March 20-21, 1995.A hierarchical approach to protein folding is employed to examine the folding pathway and predict the quaternary structure of the GCN4 leucine zipper. Structures comparable in quality to experiment have been predicted. In addition, the equilibrium between dimers, trimers and tetramers of a number of GCN4 mutants has been examined. In five out of eight cases, the simulation results are in accordance with the experimental studies of Harbury, et al
Topography Experiment (TOPEX) Software Document Series Volume 7: TOPEX Mission Radar Altimeter Engineering Assessment Report, February 1994
This document describes the GSFC/WFF analysis of the on-orbit engineering data from the TOPEX radar altimeter, to establish altimeter performance. In accordance with Project guidelines, neither surface truth nor precision orbital data are used for the engineering assessment of the altimeter. The use of such data would imply not only a more intensive and complete performance evaluation, but also a calibration. Such evaluations and.calibrations are outside the scope of this document and will be presented in a separate Verification Report
Modal expansions and non-perturbative quantum field theory in Minkowski space
We introduce a spectral approach to non-perturbative field theory within the
periodic field formalism. As an example we calculate the real and imaginary
parts of the propagator in 1+1 dimensional phi^4 theory, identifying both
one-particle and multi-particle contributions. We discuss the computational
limits of existing diagonalization algorithms and suggest new quasi-sparse
eigenvector methods to handle very large Fock spaces and higher dimensional
field theories.Comment: new material added, 12 pages, 6 figure
An Implicit Membrane Generalized Born Theory for the Study of Structure, Stability, and Interactions of Membrane Proteins
This is the published version. Copyright 2003 by Elsevier.Exploiting recent developments in generalized Born (GB) electrostatics theory, we have reformulated the calculation of the self-electrostatic solvation energy to account for the influence of biological membranes. Consistent with continuum Poisson-Boltzmann (PB) electrostatics, the membrane is approximated as an solvent-inaccessible infinite planar low-dielectric slab. The present membrane GB model closely reproduces the PB electrostatic solvation energy profile across the membrane. The nonpolar contribution to the solvation energy is taken to be proportional to the solvent-exposed surface area (SA) with a phenomenological surface tension coefficient. The proposed membrane GB/SA model requires minor modifications of the pre-existing GB model and appears to be quite efficient. By combining this implicit model for the solvent/bilayer environment with advanced computational sampling methods, like replica-exchange molecular dynamics, we are able to fold and assemble helical membrane peptides. We examine the reliability of this model and approach by applications to three membrane peptides: melittin from bee venom, the transmembrane domain of the M2 protein from Influenza A (M2-TMP), and the transmembrane domain of glycophorin A (GpA). In the context of these proteins, we explore the role of biological membranes (represented as a low-dielectric medium) in affecting the conformational changes in melittin, the tilt of transmembrane peptides with respect to the membrane normal (M2-TMP), helix-to-helix interactions in membranes (GpA), and the prediction of the configuration of transmembrane helical bundles (GpA). The present method is found to perform well in each of these cases and is anticipated to be useful in the study of folding and assembly of membrane proteins as well as in structure refinement and modeling of membrane proteins where a limited number of experimental observables are available
Implicit solvation based on generalized Born theory in different dielectric environments
Copyright 2004 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in The Journal of Chemical Physics and may be found at http://dx.doi.org/10.1063/1.1631258.In this paper we are investigating the effect of the dielectric environment on atomic Born radii used in generalized Born (GB) methods. Motivated by the Kirkwood expression for the reaction field of a single off-center charge in a spherical cavity, we are proposing extended formalisms for the calculation of Born radii as a function of external and internal dielectric constants. We demonstrate that reaction field energies calculated from environmentally dependent Born radii lead to much improved agreement with Poisson–Boltzmann solutions for low dielectric external environments, such as biological membranes or organic solvent, compared to previous methods where the calculation of Born radii does not depend on the environment. We also examine how this new approach can be applied for the calculation of transfer free energies from vacuum to a given external dielectric for a system with an internal dielectric larger than one. This has not been possible with standard GB theory but is relevant when scoring minimized or average structures with implicit solvent
Membrane Assembly of Simple Helix Homo-Oligomers Studied via Molecular Dynamics Simulations
This is the publisher's version. Copyright 2007 by Elsevier.The assembly of simple transmembrane helix homo-oligomers is studied by combining a generalized Born implicit membrane model with replica exchange molecular dynamics simulations to sample the conformational space of various oligomerization states and the native oligomeric conformation. Our approach is applied to predict the structures of transmembrane helices of three proteins—glycophorin A, the M2 proton channel, and phospholamban—using only peptide sequence and the native oligomerization state information. In every case, the methodology reproduces native conformations that are in good agreement with available experimental structural data. Thus, our method should be useful in the prediction of native structures of transmembrane domains of other peptides. When we ignore the experimental constraint on the native oligomerization state and attempt de novo prediction of the structure and oligomerization state based only on sequence and simple energetic considerations, we identify the pentamer as the most stable oligomer for phospholamban. However, for the glycophorin A and the M2 proton channels, we tend to predict higher oligomers as more stable. Our studies demonstrate that reliable predictions of the structure of transmembrane helical oligomers can be achieved when the observed oligomerization state is imposed as a constraint, but that further efforts are needed for the de novo prediction of both structure and oligomeric state
Deprotonation by Dehydration: The Origin of Ammonium Sensing in the AmtB Channel
The AmtB channel passively allows the transport of NH(4) (+) across the membranes of bacteria via a “gas” NH(3) intermediate and is related by homology (sequentially, structurally, and functionally) to many forms of Rh protein (both erythroid and nonerythroid) found in animals and humans. New structural information on this channel has inspired computational studies aimed at clarifying various aspects of NH(4) (+) recruitment and binding in the periplasm, as well as its deprotonation. However, precise mechanisms for these events are still unknown, and, so far, explanations for subsequent NH(3) translocation and reprotonation at the cytoplasmic end of the channel have not been rigorously addressed. We employ molecular dynamics simulations and free energy methods on a full AmtB trimer system in membrane and bathed in electrolyte. Combining the potential of mean force for NH(4) (+)/NH(3) translocation with data from thermodynamic integration calculations allows us to find the apparent pK(a) of NH(4) (+) as a function of the transport axis. Our calculations reveal the specific sites at which its deprotonation (at the periplasmic end) and reprotonation (at the cytoplasmic end) occurs. Contrary to most hypotheses, which ascribe a proton-accepting role to various periplasmic or luminal residues of the channel, our results suggest that the most plausible proton donor/acceptor at either of these sites is water. Free-energetic analysis not only verifies crystallographically determined binding sites for NH(4) (+) and NH(3) along the transport axis, but also reveals a previously undetermined binding site for NH(4) (+) at the cytoplasmic end of the channel. Analysis of dynamics and the free energies of all possible loading states for NH(3) inside the channel also reveal that hydrophobic pressure and the free-energetic profile provided by the pore lumen drives this species toward the cytoplasm for protonation just before reaching the newly discovered site
Warm and Cold Denaturation in the Phase Diagram of a Protein Lattice Model
Studying the properties of the solvent around proteins, we propose a much
more sophisticated model of solvation than temperature-independent pairwise
interactions between monomers, as is used commonly in lattice representations.
We applied our model of solvation to a 16-monomer chain constrained on a
two-dimensional lattice. We compute a phase diagram function of the temperature
and a solvent parameter which is related to the pH of the solution. It exhibits
a native state in which the chain coalesces into a unique compact conformation
as well as a denatured state. Under certain solvation conditions, both warm and
cold denaturations occur between the native and the denatured states. A good
agreement is found with the data obtained from calorimetric experiments,
thereby validating the proposed model.Comment: 7 pages, 2 figure
Predicting extreme p K a shifts in staphylococcal nuclease mutants with constant pH molecular dynamics
Accurate computational methods of determining protein and nucleic acid p K a values are vital to understanding pH‐dependent processes in biological systems. In this article, we use the recently developed method constant pH molecular dynamics (CPHMD) to explore the calculation of highly perturbed p K a values in variants of staphylococcal nuclease (SNase). Simulations were performed using the replica exchange (REX) protocol for improved conformational sampling with eight temperature windows, and yielded converged proton populations in a total sampling time of 4 ns. Our REX‐CPHMD simulations resulted in calculated p K a values with an average unsigned error (AUE) of 0.75 pK units for the acidic residues in Δ + PHS, a hyperstable variant of SNase. For highly p K a ‐perturbed SNase mutants with known crystal structures, our calculations yielded an AUE of 1.5 pK units and for those mutants based on modeled structures an AUE of 1.4 pK units was found. Although a systematic underestimate of pK shifts was observed in most of the cases for the highly perturbed pK mutants, correlations between conformational rearrangement and plasticity associated with the mutation and error in p K a prediction was not evident in the data. This study further extends the scope of electrostatic environments explored using the REX‐CPHMD methodology and suggests that it is a reliable tool for rapidly characterizing ionizable amino acids within proteins even when modeled structures are employed. Proteins 2011; © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88038/1/23195_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/88038/2/PROT_23195_sm_SuppInfo.pd
GEOSAT Follow-On (GFO) Altimeter Document Series, Volume 9. GFO and JASON Altimeter Engineering Assessment Report Update: GFO-Acceptance to December 18, 2006, JASON-Acceptance to December 24, 2006. Version 1: June 2007
The initial GFO Altimeter Engineering Assessment Report, March 2001 (NASA/TM-2001-209984/Ver.1/Vol.1) covered the GFO performance from Launch to Acceptance (10 February 1998 to 29 November 2000). The second of the series covered the performance from Acceptance to the end of Cycle 20 (29 November 2000 to 21 November 2001). The third of the series covered the performance from Acceptance to the end of Cycle 42 (29 November 2000 to 30 November 2002). The fourth of the series covered the performance from Acceptance to the end of Cycle 64 (29 November 2000 to 17 December 2003). The fifth of the series covered performance from Acceptance to the end of Cycle 86 (29 November 2000 to 17 December 2004). The sixth of the series covered performance from Acceptance to the end of Cycle 109 (29 November 2000 to 26 December 2005). In this year's GFO report, we have begun the inclusion of analyses of the JASON altimeter. In past years, JASON and TOPEX were compared during our assessment of the TOPEX altimeter; however, with the end of the TOPEX mission, we have developed methods to report on JASON as it relates to GFO. We see no change trend between the three altimeters and conclude all three are stable based on our cross comparison analyses
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