http://www.biomedcentral.com/bmcbiophys The editor's pick of recent articles published by BMC Biophysics 2012-05-17T00:00:00Z Gluten intolerance is a condition which affects an increasing percentage of the world's population and for which the only current treatment is a restrictive gluten free diet. However could the inclusion of a particular polysaccharide, or blends of different types, help with the provision of 'safer' foods for those individuals who suffer from this condition. We review the current knowledge on the prevalence, clinical symptoms and treatment of gluten intolerance, and the use and properties of the allergens responsible. We consider the potential for dietary fibre polysaccharides to sequester peptides that are responsible for activation of the disease in susceptible individuals, and consider the potential of co-sedimentation in the analytical ultracentrifuge as a molecular probe for finding interactions strong enough to be considered as useful. http://www.biomedcentral.com/2046-1682/5/10 M Samil Kök Richard Gillis Shirley Ang David Lafond Arthur S Tatham Gary Adams Stephen E Harding BMC Biophysics 2012, 5:10 2012-05-17T00:00:00Z 10.1186/2046-1682-5-10 Safer foods for gluten intolerance? Stephen Harding and colleagues speculate on the role that the ultracentrifuge assay procedure could play in detecting non-toxic biopolymers capable of sequestering ingested gluten peptides, with the eventual aim of reducing gluten intolerance symptoms. /content/figures/2046-1682-5-10-toc.gif BMC Biophysics 2046-1682 5 10 2012-05-17T00:00:00Z PDF Background: Accurate modeling of electrostatic potential and corresponding energies becomesincreasingly important for understanding properties of biological macromolecules and theircomplexes. However, this is not an easy task due to the irregular shape of biological entitiesand the presence of water and mobile ions. Results: Here we report a comprehensive suite for the well-known Poisson-Boltzmann solver, DelPhi,enriched with additional features to facilitate DelPhi usage. The suite allows for easydownload of both DelPhi executable files and source code along with a makefile for localinstallations. The users can obtain the DelPhi manual and parameter files required for thecorresponding investigation. Non-experienced researchers can download examples containingall necessary data to carry out DelPhi runs on a set of selected examples illustrating variousDelPhi features and demonstrating DelPhi's accuracy against analytical solutions. Conclusions: DelPhi suite offers not only the DelPhi executable and sources files, examples and parameterfiles, but also provides links to third party developed resources either utilizing DelPhi orproviding plugins for DelPhi. In addition, the users and developers are offered a forum toshare ideas, resolve issues, report bugs and seek help with respect to the DelPhi package. Theresource is available free of charge for academic users from URL:http://compbio.clemson.edu/delphi.php http://www.biomedcentral.com/2046-1682/5/9 Lin Li Chuan Li Subhra Sarkar Jie Zhang Shawn Witham Zhe Zhang Lin Wang Nicholas Smith Marharyta Petukh Emil Alexov BMC Biophysics 2012, 5:9 2012-05-14T00:00:00Z 10.1186/2046-1682-5-9 An oracle for calculating electrostatic interactions The DelPhi package is a comprehensive and user-friendly suite of tools for modelling electrostatic potentials in macromolecules using the Poisson-Boltzmann Equation, and is now enriched with additional features for greater usability. /content/figures/2046-1682-5-9-toc.gif BMC Biophysics 2046-1682 5 9 2012-05-14T00:00:00Z PDF Background: Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. Results: In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding protein), a kinase inhibitor with multiple partners. Conclusions: An approach using arbitrary docking, and based solely on physical properties, can successfully identify biologically pertinent protein interfaces. http://www.biomedcentral.com/2046-1682/5/7 Juliette Martin Richard Lavery BMC Biophysics 2012, 5:7 2012-05-06T00:00:00Z 10.1186/2046-1682-5-7 Arbitrary docking targets protein interfaces Docking of target proteins against an arbitrary set of partners generally leads to non-random localization of interaction interfaces as the false complexes favor residues from true interaction sites, allowing prediction of biologically relevant protein interfaces /content/figures/2046-1682-5-7-toc.gif BMC Biophysics 2046-1682 5 7 2012-05-06T00:00:00Z PDF Background: In the classical view, cell membrane proteins undergo isotropic random motion, that is a 2D Brownian diffusion that should result in an homogeneous distribution of concentration. It is, however, far from the reality: Membrane proteins can assemble into so-called microdomains (sometimes called lipid rafts) which also display a specific lipid composition. Results: The amount of this so-called overconcentration at equilibrium is simply related to the ratio of diffusion coefficients between zones of high and low diffusion. Expanding the model to include particle interaction, we show that inhomogeneous diffusion can impact particles clusterization as well. The clusters of particles were more numerous and appear for a lower value of interaction strength in the zones of low diffusion compared to zones of high diffusion. Conclusion: Provided we assume stable viscosity heterogeneity in the membrane, our model proposes a simple mechanism to explain particle concentration heterogeneity. It has also a non-trivial impact on density of particles when interaction is added. This could potentially have an impact on membrane chemical reactions and oligomerization http://www.biomedcentral.com/2046-1682/5/6 Hedi A Soula Antoine Coulon Guillaume Beslon BMC Biophysics 2012, 5:6 2012-04-30T00:00:00Z 10.1186/2046-1682-5-6 Modeling membrane microdomains Non-homogeneous diffusion in cell membranes leads to the formation of protein/ lipid enriched microdomains in a model of membrane dynamics, with domains of high viscosity tending to gather a statistically larger proportion of diffusive particles /content/figures/2046-1682-5-6-toc.gif BMC Biophysics 2046-1682 5 6 2012-04-30T00:00:00Z PDF Background: The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature. Results: In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount. Conclusions: The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane. http://www.biomedcentral.com/2046-1682/5/5 Steven C Nelson Steven K Neeley Eric D Melonakos John D Bell David D Busath BMC Biophysics 2012, 5:5 2012-03-24T00:00:00Z 10.1186/2046-1682-5-5 Differential effects of anesthetic on lipid bilayers Steady-state anisotropy of two fluorescent probes at different depths in a lipid bilayer reveals a decrease in anisotropy with increasing isoflurane anesthetic concentration, reflecting changes in the lateral pressure profile of the membrane. /content/figures/2046-1682-5-5-toc.gif BMC Biophysics 2046-1682 5 5 2012-03-24T00:00:00Z XML Background: The V3 loop of the glycoprotein gp120 of HIV-1 plays an important role in viral entry into cells by utilizing as coreceptor CCR5 or CXCR4, and is implicated in the phenotypic tropisms of HIV viruses. It has been hypothesized that the interaction between the V3 loop and CCR5 or CXCR4 is mediated by electrostatics. We have performed hierarchical clustering analysis of the spatial distributions of electrostatic potentials and charges of V3 loop structures containing consensus sequences of HIV-1 subtypes. Results: Although the majority of consensus sequences have a net charge of +3, the spatial distribution of their electrostatic potentials and charges may be a discriminating factor for binding and infectivity. This is demonstrated by the formation of several small subclusters, within major clusters, which indicates common origin but distinct spatial details of electrostatic properties. Some of this information may be present, in a coarse manner, in clustering of sequences, but the spatial details are largely lost. We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences. We also make correlations between clustering of electrostatic potentials and net charge, coreceptor selectivity, global prevalence, and geographic distribution. Finally, we interpret coreceptor selectivity based on the N6X7T8|S8X9 sequence glycosylation motif, the specific positive charge location according to the 11/24/25 rule, and the overall charge and electrostatic potential distribution. Conclusions: We propose that in addition to the sequence and the net charge of the V3 loop of each subtype, the spatial distributions of electrostatic potentials and charges may also be important factors for receptor recognition and binding and subsequent viral entry into cells. This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex. We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge. http://www.biomedcentral.com/2046-1682/5/3 Aliana López de Victoria Chris A Kieslich Apostolos K Rizos Elias Krambovitis Dimitrios Morikis BMC Biophysics 2012, 5:3 2012-02-07T00:00:00Z 10.1186/2046-1682-5-3 Electrostatic properties of HIV-1 gp120 The spatial distributions of electrostatic potentials and charges in the V3 loop of HIV-1 protein gp120 may be responsible for both long- and short-range interactions with co-receptors, ultimately affecting viral entry into cells /content/figures/2046-1682-5-3-toc.gif BMC Biophysics 2046-1682 5 3 2012-02-07T00:00:00Z XML Background: The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces. Results: We first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated. Conclusions: Our study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high-affinity interaction with ephrins because the weak interaction with small molecule was found to be insufficient to trigger the transition. Our results therefore highlight the key role of protein dynamics in Eph-ephrin signalling and would benefit future design of agonists/antagonists targeting Eph receptors. http://www.biomedcentral.com/2046-1682/5/2 Haina Qin Liangzhong Lim Jianxing Song BMC Biophysics 2012, 5:2 2012-01-25T00:00:00Z 10.1186/2046-1682-5-2 Intrinsic dynamics of the ephrin receptor EphA4 Structural determination of the EphA4 ligand binding domain provides the first experimental and computational evidence that intrinsic dynamics are most likely to be responsible for the observed high conformational diversity that mediates binding affinity and specificity. /content/figures/2046-1682-5-2-toc.gif BMC Biophysics 2046-1682 5 2 2012-01-25T00:00:00Z XML Background: Protein-lipid interactions play essential roles in the conformational stability and biological functions of membrane proteins. However, few of the previous computational studies have taken into account the atomic details of protein-lipid interactions explicitly. Results: To gain an insight into the molecular mechanisms of the recognition of lipid molecules by membrane proteins, we investigated amino acid propensities in membrane proteins for interacting with the head and tail groups of lipid molecules. We observed a common pattern of lipid tail-amino acid interactions in two different data sources, crystal structures and molecular dynamics simulations. These interactions are largely explained by general lipophilicity, whereas the preferences for lipid head groups vary among individual proteins. We also found that membrane and water-soluble proteins utilize essentially an identical set of amino acids for interacting with lipid head and tail groups. Conclusions: We showed that the lipophilicity of amino acid residues determines the amino acid preferences for lipid tail groups in both membrane and water-soluble proteins, suggesting that tightly-bound lipid molecules and lipids in the annular shell interact with membrane proteins in a similar manner. In contrast, interactions between lipid head groups and amino acids showed a more variable pattern, apparently constrained by each protein's specific molecular function. http://www.biomedcentral.com/2046-1682/4/21 Mizuki Morita AVSK Katta Shandar Ahmad Takaharu Mori Yuji Sugita Kenji Mizuguchi BMC Biophysics 2011, 4:21 2011-12-14T00:00:00Z 10.1186/2046-1682-4-21 Lipid preferences of membrane proteins Tightly-bound lipid molecules and lipids in the annular shell interact with membrane proteins in a similar manner, largely explained by general lipophilicity, that suggests a common pattern of lipid tail-amino acid interactions /content/figures/2046-1682-4-21-toc.gif BMC Biophysics 2046-1682 4 21 2011-12-14T00:00:00Z XML Background: DNA is a carrier of biological information. The hybridization process, the formation of the DNA double-helix from single-strands with complementary sequences, is important for all living cells. DNA microarrays, among other biotechnologies such as PCR, rely on DNA hybridization. However, to date the thermodynamics of hybridization is only partly understood. Here we address, experimentally and theoretically, the hybridization of oligonucleotide strands of unequal lengths, which form a bulged loop upon hybridization. For our study we use in-house synthesized DNA microarrays. Results: We synthesize a microarray with additional thymine bases in the probe sequence motifs so that bulged loops occur upon target hybridization. We observe a monotonic decrease of the fluorescence signal of the hybridized strands with increasing length of the bulged loop. This corresponds to a decrease in duplex binding affinity within the considered loop lengths of one to thirteen bases. By varying the position of the bulged loop along the DNA duplex, we observe a symmetric signal variation with respect to the center of the strand. We reproduce the experimental results well using a molecular zipper model at thermal equilibrium. However, binding states between both strands, which emerge through duplex opening at the position of the bulged loop, need to be taken into account. Conclusions: We show that stable DNA duplexes with a bulged loop can form from short strands of unequal length and they contribute substantially to the fluorescence intensity from the hybridized strands on a microarray. In order to reproduce the result with the help of equilibrium thermodynamics, it is essential (and to a good approximation sufficient) to consider duplex opening not only at the ends but also at the position of the bulged loop. Although the thermodynamic parameters used in this study are taken from hybridization experiments in solution, these parameters fit our DNA microarray data well. http://www.biomedcentral.com/2046-1682/4/20 Christian Trapp Marc Schenkelberger Albrecht Ott BMC Biophysics 2011, 4:20 2011-12-13T00:00:00Z 10.1186/2046-1682-4-20 Hybridization of DNA targets with a bulged loop Stable DNA duplexes with a bulged loop can form from short strands of unequal length with duplex stability decreasing monotonically with the length of the bulged loop, contributing substantially to microarray fluorescence intensity /content/figures/2046-1682-4-20-toc.gif BMC Biophysics 2046-1682 4 20 2011-12-13T00:00:00Z XML