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Publications
Gopinath Subramanian and Sachin Shanbhag, Self-Diffusion in Binary Blends of Cyclic and Linear Polymers. Journal: Macromolecules, pages 7239–724, 2008. Abstract [+]: A lattice model is used to estimate the self-diffusivity of entangled cyclic and linear polymers in blends of varying compositions. To interpret simulation results, we suggest a minimal constraint release model for the motion of a cyclic polymer infiltrated by neighboring linear chains. Both the simulation and recently reported experimental data on entangled DNA solutions support the simple model over a wide range of blend compositions, concentrations, and molecular weights.
Click here for more informationNylander, J. A., J.C. Wilgenbusch, D. L. Warren, D. L. Swofford, AWTY (Are We There Yet): a system for graphical exploration of MCMC convergence in Bayesian phylogenetics. Journal: Bioinformatics, pages 581–583, 2008. Abstract [+]: A key element to a successful Markov chain Monte Carlo (MCMC) inference is the programming and run performance of the Markov chain. However, the explicit use of quality assessments of the MCMC simulations, convergence diagnostics, in phylogenetics is still uncommon. Here we present a simple tool that uses the output from MCMC simulations and visualizes a number of properties of primary interest in a Bayesian phylogenetic analysis, such as convergence rates of posterior split probabilities and branch lengths. Graphical exploration of the output from phylogenetic MCMC simulations gives intuitive and often crucial information on the success and reliability of the analysis. The tool presented here complements convergence diagnostics already available in other software packages primarily designed for other applications of MCMC. Importantly, the common practice of using trace-plots of a single parameter or summary statistic, such as the likelihood score of sampled trees, can be misleading for assessing the success of a phylogenetic MCMC simulation.
Click here for more informationVan Dyke, Donald F., COAPS/FSU Real Time Gulf of Mexico 4 km WRF-ARW Atmospheric Model. Dissertation/Thesis 2008. Abstract [+]: There are several goals of these simulations, and the web page will see new graphics and features over time. The primary goal is to attempt to address the continuing struggle that current operational numerical models have with the correct prediction of the moisture content of the return flow airmass over the Gulf of Mexico after a cold-air outbreak during the cool season (Nov-Mar). Cold-air outbreaks are associated with significant changes in the sea surface temperature over a wide region of the Gulf of Mexico. This cooling of the sea surface temperature by as much as several degrees relative to the initial temperature field should be reflected in differences in the air-sea fluxes of latent and sensible heat, which then may be manifested in different boundary layer temperature and humidity structures. Errors in forecasted surface winds and the use of non-varying sea surface temperatures are identified as possible influences on the incorrect moisture forecast (Lewis 2007). Thus, it is speculated that the inclusion of this variation in sea surface temperature will influence the nature of the return flow airmass. As such, the ultimate goal is to work toward a fully coupled high resolution WRF/HYCOM (HYbrid Coordinate Ocean Model) atmosphere/ocean modeling system over the Gulf of Mexico.
Click here for more informationClemens Lakner, Paul van der Mark, John P. Huelsenbeck, Bret Larget, and Fredrik Ronquist, Efficiency of Markov Chain Monte Carlo Tree Proposals in Bayesian Phylogenetics. Journal: Systematic Biology, 57(1), pages 86-103, 2008. Henry R. Winterbottom, Eric P. Chassignet, and Carol Anne Clayson, HYCOM North Atlantic Ocean Basin Forecasts. Dissertation/Thesis 2008. Abstract [+]: This page provides experimental 1-2 times daily (0000 UTC and 1200 UTC) high resolution HYbrid Coordinate Ocean Model (HYCOM) real-time WRF-ARW atmospheric forcing forecasts
for the North Atlantic basin.
Click here for more informationIsabel SanMartin, Paul van der Mark, and Fredrik Ronquist, Inferring dispersal: a Bayesian approach to phylogenetic-based island biogeography, with special reference to the Canary islands. Journal: Journal of Biogeography, 35, pages 428-449, 2008. Haidao Lin and Xiaolei Zou, Can geosynchronous imaging Fourier transform spectrometer capture vertical and temporal variability of a convective atmosphere?. Journal: J. Appl. Remote Sens., Vol. 2, 023534 (2008); DOI:10.1117/1.2980331, pages 19, 2008. Abstract [+]: Insufficient high vertical and temporal resolution data have limited the precipitation forecast skill of convective initiation. The Geosynchronous Imaging Fourier Transform Spectrometer (GIFTS), a new hyperspectral geostationary satellite measurement system, could provide top-of-atmosphere (TOA) radiances across two broad spectral regions with high-resolutions in spectral, horizontal and temporal spaces within a fixed domain. A set of modeled and observed vertical profiles of atmospheric moisture and temperature during a convective initiation (CI) event within the observing period of the International H2O Project (IHOP_2002) are used to assess the potential values of GIFTS measurements to convective precipitation forecast. First, it is shown that the model simulation captures reasonably well the movement of the precipitation bands and the gradient structures of temperature and water vapor of the convectively initiated storm. Second, the observed vertical and temporal variability of water vapor during the CI period is shown to be quite significant in the lower troposphere. The differences between observations and model simulation are also noticed. Using both the observed and the model-predicted profiles as input to GIFTS radiative transfer model (RTM), it is finally shown that the simulated GIFTS radiance could capture the high vertical and temporal variability of the real and modeled atmosphere prior to the CI, as well as the differences between observations and model forecasts. The study suggests the potential for GIFTS to make important contributions to the improvement of the forecast skill of convective precipitation.
Click here for more informationPaul van der Mark, Daniel R. Voss, and Jeff E. McDonald, High Performance Computing at FSU. Poster: SuperComputing 07, 2007. Click here for more information Harianto Tjong and Huan-Xiang Zhou, Accurate Calculations of Binding, Folding, and Transfer Free Energies by a Scaled Generalized Born Method. Journal: Journal of Chemical Theory and Computation, pages , 2008. Abstract [+]: The Poisson−Boltzmann (PB) equation is widely used for modeling solvation effects. The computational cost of PB has restricted its applications largely to single-conformation calculations. The generalized Born (GB) model provides an approximation at substantially reduced cost. Currently the best GB methods reproduce PB results for electrostatic solvation energies with errors at ~5 kcal/mol. When two proteins form a complex, the net electrostatic contributions to the binding free energy are typically of the order of 5 to 10 kcal/mol. Similarly, the net contributions of individual residues to protein folding free energy are <5 kcal/mol. Clearly in these applications the accuracy of current GB methods is insufficient. Here we present a simple scaling scheme that allows our GB method, GBr6, to reproduce PB results for binding, folding, and transfer free energies with high accuracy. From an ensemble of conformations sampled from molecular dynamics simulations, five were judiciously selected for PB calculations. These PB results were used for scaling GBr6. Tests on the binding free energies of the barnase-barstar, GTPase-WASp, and U1A-U1hpII complexes and on the folding free energy of FKBP show that the effects of point mutations calculated by scaled GBr6 are accurate to within 0.3 kcal/mol of PB results. Similar accuracy was also achieved for the free energies of transfer for ribonuclease Sa and insulin from the crystalline phase to the solution phase at various pHs. This method makes it possible to thoroughly sample the transient-complex ensemble in predicting protein binding rate constants and to incorporate conformational sampling in electrostatic modeling (such as done in the MM-GBSA approach) without loss of accuracy.
Myunggi Yi, Hugh Nymeyer, Huan X Zhou, Test of the Gouy-Chapman Theory for a Charged Lipid Membrane against Explicit-Solvent Molecular Dynamics Simulations. Journal: Physical Review Letters Vol. 101, No. 3, pages , 2008. Abstract [+]: A wealth of experimental data has verified the applicability of the Gouy-Chapman (GC) theory to charged lipid membranes. Surprisingly, a validation of GC by molecular dynamics (MD) simulations has been elusive. Here, we report a test of GC against extensive MD simulations of an anionic lipid bilayer solvated by water at different concentrations of NaCl or KCl. We demonstrate that the ion distributions from the simulations agree remarkably well with GC predictions when information on the adsorption of counterions to the bilayer is incorporated.
Click here for more informationMyunggi Yi, Timothy A. Cross, and Huan-Xiang Zhou, A Secondary Gate As a Mechanism for Inhibition of the M2 Proton Channel by Amantadine. Journal: Journal of Physical Chemistry B Vol. 112, No. 27, pages 7977-7979, 2008. Abstract [+]: Abstract: The mechanism of inhibition of the influenza A virus M2 proton channel by the antiviral drug amantadine has been under intense investigation. The importance of a mechanistic understanding is heightened by the prevalence of amantadine-resistant mutations. To gain mechanistic insight at the molecular level, we carried out extensive molecular dynamics simulations of the tetrameric M2 proton channel in both apo and amantadine-bound forms in a lipid bilayer. The simulation of the apo form revealed that Val27 from the four M2 subunits can form a secondary gate near the channel entrance and break the water wire in the channel pore. This gate arises from physical occlusion and the elimination of hydrogen-bonding partners for water molecules. In the presence of amantadine, the secondary gate formed by Val27 and the drug molecule lying just below form an extended blockage, which breaks the water wire throughout the simulation. The location and orientation of amantadine inside of the channel pore as found in our simulation are supported by a host of experimental observations. Our study suggests a novel role for Val27 in the inhibition of the M2 proton channel by amantadine.
Click here for more informationMyunggi Yi, Harianto Tjong, and Huan-Xiang Zhou, Spontaneous conformational change and toxin binding in a7 acetylcholine receptor: Insight into channel activation and inhibition. Journal: Proc. Natl. Acad. Sci Vol 105, No. 34, pages 8280-8285, 2008. Abstract [+]: Nicotinic AChRs (nAChRs) represent a paradigm for ligand-gated ion channels. Despite intensive studies over many years, our understanding of the mechanisms of activation and inhibition for nAChRs is still incomplete. Here, we present molecular dynamics (MD) simulations of the α7 nAChR ligand-binding domain, both in apo form and in α-Cobratoxin-bound form, starting from the respective homology models built on crystal structures of the acetylcholine-binding protein. The toxin-bound form was relatively stable, and its structure was validated by calculating mutational effects on the toxin-binding affinity. However, in the apo form, one subunit spontaneously moved away from the conformation of the other four subunits. This motion resembles what has been proposed for leading to channel opening. At the top, the C loop and the adjacent β7-β8 loop swing downward and inward, whereas at the bottom, the F loop and the C terminus of β10 swing in the opposite direction. These swings appear to tilt the whole subunit clockwise. The resulting changes in solvent accessibility show strong correlation with experimental results by the substituted cysteine accessibility method upon addition of acetylcholine. Our MD simulation results suggest a mechanistic model in which the apo form, although predominantly sampling the “closed” state, can make excursions into the “open” state. The open state has high affinity for agonists, leading to channel activation, whereas the closed state upon distortion has high affinity for antagonists, leading to inhibition.
Click here for more informationHarianto Tjong and Huan-Xiang Zhou, Prediction of Protein Solubility from Calculation of Transfer Free Energy. Journal: Biophysical Journal Vol 95, pages 2601-2609, 2008. Abstract [+]: Solubility plays a major role in protein purification, and has serious implications in many diseases. We studied the effects of pH and mutations on protein solubility by calculating the transfer free energy from the condensed phase to the solution phase. The condensed phase was modeled as an implicit solvent, with a dielectric constant lower than that of water. To account for the effects of pH, the protonation states of titratable side chains were sampled by running constant-pH molecular dynamics simulations. Conformations were then selected for calculations of the electrostatic solvation energy: once for the condensed phase, and once for the solution phase. The average transfer free energy from the condensed phase to the solution phase was found to predict reasonably well the variations in solubility of ribonuclease Sa and insulin with pH. This treatment of electrostatic contributions combined with a similar approach for nonelectrostatic contributions led to a quantitative rationalization of the effects of point mutations on the solubility of ribonuclease Sa. This study provides valuable insights into the physical basis of protein solubility.
Click here for more informationHarianto Tjong and Huan-Xiang Zhou, On the Dielectric Boundary in Poisson-Boltzmann Calculations. Journal: J. Chem. Theory Comput Vol. 4, No. 3, pages 507-514, 2008. Abstract [+]: In applying the Poisson-Boltzmann (PB) equation for calculating the electrostatic free energies of solute molecules, an open question is how to specify the boundary between the low-dielectric solute and the high-dielectric solvent. Two common specifications of the dielectric boundary, as the molecular surface (MS) or the van der Waals (vdW) surface of the solute, give very different results for the electrostatic free energy of the solute. With the same atomic radii, the solute is more solvent-exposed in the vdW specification. One way to resolve the difference is to use different sets of atomic radii for the two surfaces. The radii for the vdW surface would be larger in order to compensate for the higher solvent exposure. Here we show that radius reparametrization required for bringing MS-based and vdW-based PB results to agreement is solute-size dependent. The difference in atomic radii for individual amino acids as solutes is only 2-5% but increases to over 20% for proteins with ~200 residues. Therefore two sets of radii that yield identical MS-based and vdW-based PB results for small solutes will give very different PB results for large solutes. This finding raises issues about two common practices. The first is the use of atomic radii, which are parametrized against either experimental solvation data or data obtained from explicit-solvent simulations on small compounds, for PB calculations on proteins. The second is the parametrization of vdW-based generalized Born models against MS-based PB results.
Click here for more informationHugh Nymeyer and Huan-Xiang Zhou, A Method to Determine Dielectric Constants in Nonhomogeneous Systems: Application to Biological Membranes. Journal: Biophysical Journal Vol 94, pages 1185-1193, 2008. Abstract [+]: Continuum electrostatic models have had quantitative success in describing electrostatic-mediated phenomena on atomistic scales; however, there continues to be significant disagreement about how to assign dielectric constants in mixed, nonhomogeneous systems. We introduce a method for determining a position-dependent dielectric profile from molecular dynamics simulations. In this method, the free energy of introducing a test charge is computed two ways: from a free energy perturbation calculation and from a numerical solution to Poisson's Equation. The dielectric profile of the system is then determined by minimizing the discrepancy between these two calculations simultaneously for multiple positions of the test charge. We apply this method to determine the dielectric profile of a lipid bilayer surrounded by water. We find good agreement with dielectric models for lipid bilayers obtained by other approaches. The free energy of transferring an ion from bulk water to the lipid bilayer computed from the atomistic simulations indicates that large errors are introduced when the bilayer is represented as a single slab of low dielectric embedded in the higher-dielectric solvent. Significant improvement results from introducing an additional layer of intermediate dielectric (~3) on each side of the low dielectric core extending from ~12 Å to 18 Å. A small dip in transfer free energy just outside the lipid headgroups indicates the presence of a very high dielectric. These results have implications for the design of implicit membrane models and our understanding of protein-membrane interactions.
Click here for more informationSanbo Qin and Huan-Xiang Zhou, Prediction of Salt and Mutational Effects on the Association Rate of U1A Protein and U1 Small Nuclear RNA Stem/Loop II. Journal: J. Phys. Chem. B Vol 112, N o. 19, pages 5955-5960, 2008. Abstract [+]: We have developed a computational approach for predicting protein-protein association rates (Alsallaq and Zhou, Structure 2007, 15, 215). Here we expand the range of applicability of this approach to protein-RNA binding and report the first results for protein-RNA binding rates predicted from atomistic modeling. The system studied is the U1A protein and stem/loop II of the U1 small nuclear RNA. Experimentally it was observed that the binding rate is significantly reduced by increasing salt concentration while the dissociation changes little with salt concentration, and charges distant from the binding site make marginal contribution to the binding rate. These observations are rationalized. Moreover, predicted effects of salt and charge mutations are found to be in quantitative agreement with experimental results.
Click here for more informationPing Zhu, Hanspeter Winkler, Kenneth A. Taylor, and Kenneth H. Roux., Cryoelectron tomography of HIV-1 envelope spikes: further evidence for tripod-like legs. Journal: PLoS Pathogens, pages (in press), 2008. Jason O'Donnel, Kenneth A. Taylor & Michael S. Chapman., Adeno-Associated Virus-2 and its primary cellular receptor ? cryo-EM structure of a heparin complex. Journal: J. Virology, pages submitted, 2008. Mikolai I. Fajer, Hongzhi Li, Wei Yang, and Piotr G. Fajer, Mapping Electron Paramagnetic Resonance Spin Label Conformations by the Simulated Scaling Method. Journal: Journal of the American Chemical Society Vol. 129, No. 45, pages 13840-1384, 2007. Abstract [+]: In order to efficiently simulate spin label behavior when attached to the protein backbone we developed a novel approach that enhances local conformational sampling. The simulated scaling (SS) approach (Li, H., et al. J. Chem. Phys. 2007, 126, 24106) couples the random walk of a potential scaling parameter and molecular dynamics in the framework of hybrid Monte Carlo. This approach allows efficient barrier crossings between conformations. The method retains the thermodynamic detailed balance allowing for determination of relative free energies between various conformations. The accuracy of our method was validated by comparison with the recently resolved X-ray crystal structure of a spin labeled T4 lysozyme in which the spin label was in the interior of the protein. Consistent potentials of mean force (PMF) are obtained for the spin label torsion angles to illustrate their behavior in various protein environments: surface, semiburied, and buried. These PMFs reflect the experimentally observed trends and provide the rationale for the spin label dynamics. We have used this method to compare an implicit and explicit solvent model in spin label modeling. The implicit model, which is computationally faster, was found to be in excellent agreement with the explicit solvent treatment. Based on this collection of results, we believe that the presented approach has great potential in the general strategy of describing the behavior of the spin label using molecular modeling and using this information in the interpretation of EPR measurements in terms of protein conformation and dynamics.
Click here for more informationJin Wang, Xiliang Zheng, Yongliang Yang, Dale Drueckhammer, Wei Yang, and Gennardy Verkhi, Quantifying Intrinsic Specificity: A Potential Complement to Affinity in Drug Screening. Journal: Physical Review Letters Vol. 99, No. 19, pages , 2007. Abstract [+]: We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.
Click here for more informationBernd A. Berg and Wei Yang, Numerical calculation of the combinatorial entropy of partially ordered ice. Journal: The Journal of Chemical Physics Vol. 127, No. 22, pages , 2007. Abstract [+]: Using a one-parameter case as an example, we demonstrate that multicanonical simulations allow for accurate estimates of the residual combinatorial entropy of partially ordered ice. For the considered case, corrections to an (approximate) analytical formula are found to be small, never exceeding 0.5%. The method allows one as well to calculate combinatorial entropies for other systems
Click here for more informationDonghong Min and Wei Yang, A divide-and-conquer strategy to improve diffusion sampling in generalized ensemble simulations. Journal: The Journal of Chemical Physics Vol. 128, No. 9, pages , 2008. Abstract [+]: Generalized ensemble simulations generally suffer from the associated diffusion-sampling problem; the increased entropic barrier can greatly abolish sampling efficiency, in particular, with the increase of number of degrees of freedom in the target conformational space. Taking advantage of the recent simulated scaling method, we formulate a divide-and-conquer sampling strategy to solve this problem so as to robustly improve the sampling efficiency in generalized ensemble simulations. In the present method, the target conformational space sampling enhancement is decomposed to the sampling enhancements of several subconformational regions, and multiple independent SS simulations are performed to establish the individual sampling enhancement for each of the subconformational regions; in order to realize the global importance sampling, structure exchanges among these replicas are performed based on the Monte Carlo acceptance/rejection procedure. As demonstrated in our studies, the present divide-and-conquer sampling algorithm, named by us as “simulated scaling based variant Hamiltonian replica exchange method,” has superior sampling capability so as to possibly play an essential role in dealing with the present bottleneck of generalized ensemble method developments: the system size limitations
Click here for more informationDonghong Min, Hongzhi Li, Guohui Li, Bernd A Berg, Marcia O Fenley, Wei Yang, fficient sampling of ion motions in molecular dynamics simulations on DNA: Variant Hamiltonian replica exchange method. Journal: Chemical Physics Letters Volume 454, Issues 4-6, pages 391-395, 2008. Abstract [+]: Counterions play an important role in biomolecular functions. Although molecular dynamics simulations have been applied on various nucleic acids, accurate and efficient descriptions of ion motions around DNA or RNA are still challenging, largely due to ions' slow mobility. Here, a variant Hamiltonian replica exchange method was developed to achieve efficient sampling of ion motions. Based on the present approach, the results from our model study on classical Drew-Dickerson B-DNA dodecamer show remarkable agreements with experimental measurements and nonlinear Poisson-Boltzmann predictions. Due to the employment of this variant Hamiltonian replica exchange method, these amazing agreements can be achieved within a short simulation time (900 ps).
Click here for more informationDonghong Min and Wei Yang, Energy difference space random walk to achieve fast free energy calculations. Journal: The Journal of Chemical Physics Vol. 128, No. 19, pages , 2008. Abstract [+]: A method is proposed to efficiently obtain free energy differences. In the present algorithm, free energy calculations proceed by the realization of an energy difference space random walk. Thereby, this algorithm can greatly improve the sampling of the regions in phase space where target states overlap
Click here for more informationLianqing Zheng and Wei Yang, Essential energy space random walks to accelerate molecular dynamics simulations: Convergence improvements via an adaptive-length self-healing strategy. Journal: The Journal of Chemical Physics Vol. 129, No. 1, pages , 2008. Abstract [+]: Recently, accelerated molecular dynamics (AMD) technique was generalized to realize essential energy space random walks so that further sampling enhancement and effective localized enhanced sampling could be achieved. This method is especially meaningful when essential coordinates of the target events are not priori known; moreover, the energy space metadynamics method was also introduced so that biasing free energy functions can be robustly generated. Despite the promising features of this method, due to the nonequilibrium nature of the metadynamics recursion, it is challenging to rigorously use the data obtained at the recursion stage to perform equilibrium analysis, such as free energy surface mapping; therefore, a large amount of data ought to be wasted. To resolve such problem so as to further improve simulation convergence, as promised in our original paper, we are reporting an alternate approach: the adaptive-length self-healing (ALSH) strategy for AMD simulations; this development is based on a recent self-healing umbrella sampling method. Here, the unit simulation length for each self-healing recursion is increasingly updated based on the Wang–Landau flattening judgment. When the unit simulation length for each update is long enough, all the following unit simulations naturally run into the equilibrium regime. Thereafter, these unit simulations can serve for the dual purposes of recursion and equilibrium analysis. As demonstrated in our model studies, by applying ALSH, both fast recursion and short nonequilibrium data waste can be compromised. As a result, combining all the data obtained from all the unit simulations that are in the equilibrium regime via the weighted histogram analysis method, efficient convergence can be robustly ensured, especially for the purpose of free energy surface mapping.
Click here for more informationLianqing Zheng, Irina O. Carbone and Alexey Lugovskoy, Bernd A. Berg, and Wei Yang, A hybrid recursion method to robustly ensure convergence efficiencies in the simulated scaling based free energy simulations. Journal: The Journal of Chemical Physics Vol. 129, No. 3, pages , 2008. Abstract [+]: Recently, we developed an efficient free energy simulation technique, the simulated scaling (SS) method [H. Li et al., J. Chem. Phys. 126, 024106 (2007)], in the framework of generalized ensemble simulations. In the SS simulations, random walks in the scaling parameter space are realized so that both phase space overlap sampling and conformational space sampling can be simultaneously enhanced. To flatten the distribution in the scaling parameter space, in the original SS implementation, the Wang–Landau recursion was employed due to its well-known recursion capability. In the Wang–Landau recursion based SS free energy simulation scheme, at the early stage, recursion efficiencies are high and free energy regions are quickly located, although at this stage, the errors of estimated free energy values are large; at the later stage, the errors of estimated free energy values become smaller, however, recursions become increasingly slow and free energy refinements require very long simulation time. In order to robustly resolve this efficiency problem during free energy refinements, a hybrid recursion strategy is presented in this paper. Specifically, we let the Wang–Landau update method take care of the early stage recursion: the location of target free energy regions, and let the adaptive reweighting method take care of the late stage recursion: the refinements of free energy values. As comparably studied in the model systems, among three possible recursion procedures, the adaptive reweighting recursion approach is the least favorable one because of its low recursion efficiency during free energy region locations; and compared to the original Wang–Landau recursion approach, the proposed hybrid recursion technique can be more robust to guarantee free energy simulation efficiencies
Click here for more informationD. Min, H. Josephine, H. Li, C. Lakner, I. Macpherson, G. Naylor, D. Swofford, L. Hedstrom, W. Yang, An Enzymatic Atavist Revealed in Dual Pathways for Water Activation. Journal: PLoS Biology, Vol. 6, No. 8, pages , 2008. Abstract [+]: Inosine monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the biosynthesis of guanine nucleotides. This reaction involves two different chemical transformations, an NAD-linked redox reaction and a hydrolase reaction, that utilize mutually exclusive protein conformations with distinct catalytic residues. How did Nature construct such a complicated catalyst? Here we employ a “Wang-Landau” metadynamics algorithm in hybrid quantum mechanical/molecular mechanical (QM/MM) simulations to investigate the mechanism of the hydrolase reaction. These simulations show that the lowest energy pathway utilizes Arg418 as the base that activates water, in remarkable agreement with previous experiments. Surprisingly, the simulations also reveal a second pathway for water activation involving a proton relay from Thr321 to Glu431. The energy barrier for the Thr321 pathway is similar to the barrier observed experimentally when Arg418 is removed by mutation. The Thr321 pathway dominates at low pH when Arg418 is protonated, which predicts that the substitution of Glu431 with Gln will shift the pH-rate profile to the right. This prediction is confirmed in subsequent experiments. Phylogenetic analysis suggests that the Thr321 pathway was present in the ancestral enzyme, but was lost when the eukaryotic lineage diverged. We propose that the primordial IMPDH utilized the Thr321 pathway exclusively, and that this mechanism became obsolete when the more sophisticated catalytic machinery of the Arg418 pathway was installed. Thus, our simulations provide an unanticipated window into the evolution of a complex enzyme.
Click here for more informationZheng, L. and Yang, W, On the simulated scaling based free energy simulations: Adaptive optimization of the scaling parameter. Journal: The Journal of Chemical Physics, pages (in press), 2008. Mrinal K Biswas and T N Krishnamurti, Modulation of African waves from the advection of upper level moisture from the Tropical Easterly Jet. Poster: AMS 28th Conference on Hurricanes and Tropical Meteorology, 2008. Abstract [+]: Many Atlantic hurricanes develop from African waves and moves westward over the Atlantic Ocean. The impact of upper level moisture from the Asian summer monsoon region on the African waves is addressed in this study. Sensitivity experiments were done with the PSU/NCAR MM5 model to see the impact of upper level moisture from the Tropical Easterly Jet on the African waves. The integration domain spanned the whole of Africa and run with 5 km resolution. Results show that reducing the moisture at the eastern African boundary decreases the rainfall over Africa and modulates the amplitude of the African waves. Forecasts from the FSU Global Spectral model was used to compute the kinetic energy of the African waves. Numerical experiments were separately performed when the monsoonal upper level moisture is low and then compared when it is high. The kinetic energy and the magnitude of the waves were more when the upper level moisture was greater. Our studies indicate that the growth and development of the African waves is modulated by the advection of moisture from the Asian summer monsoon. The study clearly shows the connection between the Asian summer monsoon and African waves and thus affecting the hurricanes in the Atlantic.
Click here for more informationBenjamin A. Schenkel and T.N. Krishnamurti, Conversion from Shear to Curvature Vorticity and Hurricane Evolution. Dissertation/Thesis 2008. Benjamin A. Schenkel and T.N. Krishnamurti, Conversion from Shear to Curvature Vorticity, Organization of Convection, and Hurricane Genesis. Poster: Tropical Meteorology Special Symposium, 2008. Abstract [+]: This study examines the exchange between shear and curvature vorticity and the resulting organization of convection that is central to the formation of tropical cyclones from African Waves. Horizontal shear instability results in a strong transfer of shear vorticity into curvature vorticity, which implies a small radius of curvature of flow or an “organization of convection.” As curvature is maximized and convection organizes, convective heat release based baroclinic processes start to dominate in the genesis of the storm. This study uses high-resolution satellite data in combination with model data for Hurricane Nate (2005) and a non-developing African Easterly Wave to show that vorticity conversions are responsible for the organization of convection. Cloud liquid water is calculated from brightness temperatures using the algorithm given by Wentz (1997) from AQUA, the DMSP series, and TRMM at resolutions of 0.25º. These datasets are used to show that convection is organizing by displaying a time series of the growth of the power of the azimuthal wavenumber structure of cloud liquid water. Shear to curvature vorticity ratios are then computed from the MM5 at a resolution of 0.03º using the equations given by Bell and Keyser (1993). Contributions to vorticity exchanges from barotropic, baroclinic, and diabatic processes will be examined using a modified version of the MM5.
Click here for more informationDukhovskoy, D.S., S.L. Morey, P.J. Martin, J.J. O’Brien, C. Cooper, Application of a vanishing, quasi-sigma, vertical coordinate for simulation of high-speed, deep currents over the Sigsbee Escarpment in the Gulf of Mexico. Journal: Ocean Modelling, pages , 2008. Abstract [+]: Recent observations over the Sigsbee Escarpment in the Gulf of Mexico have revealed extremely energetic deep currents (near 1 m s-1), which are trapped along the escarpment. Both scientific interest and engineering needs demand dynamical understanding of these extreme events. A primary objective of this study is to develop an appropriate model of the Sigsbee Escarpment region that will be used to study the ocean dynamics in the region, aid in analysis of the observational data, and suggest possible mechanisms of the phenomenon. The very steep slope of the Sigsbee Escarpment (0.05 - 0.1) limits the application of ocean models with traditional terrain-following (sigma) vertical coordinates, which may represent the very complicated topography in the region adequately, can result in large truncation errors during calculation of the horizontal pressure gradient. A new vertical coordinate system, termed a vanishing quasi-sigma coordinate, is implemented in the Navy Coastal Ocean Model for application to the Sigsbee Escarpment region. Vertical coordinate surfaces for this grid have noticeably gentler slopes than a traditional sigma grid, while still following the terrain near the ocean bottom. The new vertical grid is tested with a suite of numerical experiments and compared to a classical sigma-layer model. The numerical error is substantially reduced in the model with the new vertical grid. A one-year, realistic, numerical simulation is performed to simulate strong, deep currents over the Escarpment using a very-high-resolution nested modeling approach. The model results are analyzed to demonstrate that the deep ocean currents in the simulation replicate the prominent dynamical features of the observed intense currents in the region.
O'Donnell J, Taylor KA, Chapman MS., Adeno-associated virus-2 and its primary cellular receptor-Cryo-EM structure of a heparin complex.. Journal: Virology, pages 434-443, 2009. Abstract [+]: Adeno-associated virus serotype 2 (AAV-2) is a leading candidate vector for gene therapy. Cell entry starts with attachment to a primary receptor, Heparan Sulfate Proteoglycan (HSPG) before binding to a co-receptor. Here, cryo-electron microscopy provides direct visualization of the virus-HSPG interactions. Single particle analysis was performed on AAV-2 complexed with a 17 kDa heparin fragment at 8.3 A resolution. Heparin density covers the shoulder of spikes surrounding viral 3-fold symmetry axes. Previously implicated, positively charged residues R(448/585), R(451/588) and R(350/487) from another subunit cluster at the center of the heparin footprint. The footprint is much more extensive than apparent through mutagenesis, including R(347/484), K(395/532) and K(390/527) that are more conserved, but whose roles have been controversial. It also includes much of a region proposed as a co-receptor site, because prior studies had not revealed heparin interactions. Heparin density bridges over the viral 3-fold axes, indicating multi-valent attachment to symmetry-related binding sites.
Click here for more informationS. H. Thompson, G. Brown, A. Kuhnle, P. A. Rikvold, and M. A. Novotny, Resolution-dependent Mechanisms for Bimodal Switching-time Distributions in Simulated Fe Nanopillars. Journal: Physical Review B, Vol. 79, pages 024429, 2009. Abstract [+]: We study the magnetization-switching statistics following reversal of the applied field for three separate computational models representing the same physical system: an iron nanopillar. The primary difference between the models is the resolution of the computational lattice and, consequently, the intrinsic parameters that must be rescaled to retain similarity to the physical system. Considering the first-passage time to zero for the magnetization component in the longitudinal (easy-axis) direction, we look for applied fields that result in bimodal distributions of this time for each computational system and compare the results to the experimental system. We observe that the relevant fluctuations leading to bimodal distributions are different for each lattice resolution and result in magnetization-switching behavior that is unique to each computational model. Correct model resolution is thus essential for obtaining reliable numerical results for the system dynamics.
Click here for more information# Sanbo Qin and
Sanbo Qin and Huan-Xiang Zhou, Dissection of the high rate constant for the binding of a ribotoxin to the ribosome. Journal: Proc Natl Acad Sci U S A, pages 6974-6979, 2009. Abstract [+]: Restrictocin belongs to a family of site-specific ribonucleases that kill cells by inactivating the ribosome. The restrictocin-ribosome binding rate constant was observed to exceed 10(10) M(-1) s(-1). We have developed a transient-complex theory to model the binding rates of protein-protein and protein-RNA complexes. The theory predicts the rate constant as k(a) = k(a0) exp(-DeltaG(el)*/k(B)T), where k(a0) is the basal rate constant for reaching the transient complex, located at the outer boundary of the bound state, by random diffusion, and DeltaG(el)* is the average electrostatic interaction free energy of the transient complex. Here, we applied the transient-complex theory to dissect the high restrictocin-ribosome binding rate constant. We found that the binding rate of restrictocin to the isolated sarcin/ricin loop is electrostatically enhanced by approximately 300-fold, similar to results found in other protein-protein and protein-RNA complexes. The ribosome provides an additional 10,000-fold rate enhancement because of two synergistic mechanisms afforded by the distal regions of the ribosome. First, they provide additional electrostatic attraction with restrictocin. Second, they reposition the transient complex into a region where local electrostatic interactions of restrictocin with the sarcin/ricin loop are particularly favorable. Our calculations rationalize a host of experimental observations and identify a strategy for designing proteins that bind their targets with high speed.
Click here for more informationAustin Yongye, Yangmei Li, Marc Giulianotti, Yongping Yu, Richard Houghten, Karina Martinez-Mayorga, Modeling of Peptides Containing D-Amino Acids: Implications on Cyclization. Journal: Journal of Computer-Aided Molecular Design, pages DOI 10.100, 2009. Abstract [+]: Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclize in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated αL rotamers even when simulations were performed at higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L-amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.
Jianhua Lu & Ming Cai, Quantifying contributions to polar warming amplification in an idealized coupled general circulation model. Journal: Springer-Verlag 2009, pages 19, 2009. Abstract [+]: An idealized coupled general circulation model
is used to demonstrate that the surface warming due to the
doubling of CO2 can still be stronger in high latitudes than
in low latitudes even without the negative evaporation
feedback in low latitudes and positive ice-albedo feedback
in high latitudes, as well as without the poleward latent
heat transport. The new climate feedback analysis method
formulated in Lu and Cai (Clim Dyn 32:873–885, 2009)
is used to isolate contributions from both radiative and
non-radiative feedback processes to the total temperature
change obtained with the coupled GCM. These partial
temperature changes are additive and their sum is convergent
to the total temperature change. The radiative energy
flux perturbations due to the doubling of CO2 and water
vapor feedback lead to a stronger warming in low latitudes
than in high latitudes at the surface and throughout the
entire troposphere. In the vertical, the temperature changes
due to the doubling of CO2 and water vapor feedback are
maximum near the surface and decrease with height at all
latitudes. The simultaneous warming reduction in low
latitudes and amplification in high latitudes by the
enhanced poleward dry static energy transport reverses the
poleward decreasing warming pattern at the surface and in
the lower troposphere, but it is not able to do so in the
upper troposphere. The enhanced vertical moist convection
in the tropics acts to amplify the warming in the upper
troposphere at an expense of reducing the warming in the
lower troposphere and surface warming in the tropics. As a
result, the final warming pattern shows the co-existence of
a reduction of the meridional temperature gradient at the
surface and in the lower troposphere with an increase of the
meridional temperature gradient in the upper troposphere.
In the tropics, the total warming in the upper troposphere is stronger than the surface warming.
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