Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Sznajd Complex Networks

The Sznajd cellular automata corresponds to one of the simplest and yet most interesting models of complex systems. While the traditional two-dimensional Sznajd model tends to a consensus state (pro or cons), the assignment of the contrary to the dominant opinion to some of its cells during the system evolution is known to provide stabilizing feedback implying the overall system state to oscillate around null magnetization. The current article presents a novel type of geographic complex network model whose connections follow an associated feedbacked Sznajd model, i.e. the Sznajd dynamics is run over the network edges. Only connections not exceeding a maximum Euclidean distance $D$ are considered, and any two nodes within such a distance are randomly selected and, in case they are connected, all network nodes which are no further than $D$ are connected to them. In case they are not connected, all nodes within that distance are disconnected from them. Pairs of nodes are then randomly selected and assigned to the contrary of the dominant connectivity. The topology of the complex networks obtained by such a simple growth scheme, which are typically characterized by patches of connected communities, is analyzed both at global and individual levels in terms of a set of hierarchical measurements introduced recently. A series of interesting properties are identified and discussed comparatively to random and scale-free models with the same number of nodes and similar connectivity.Comment: 10 pages, 4 figure

3D model of amphioxus steroid receptor complexed with estradiol

The origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ER[alpha] are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ER[alpha] in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors

Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest

Kinetically Trapped Liquid-State Conformers of a Sodiated Model Peptide Observed in the Gas Phase

We investigate the peptide AcPheAla5LysH+, a model system for studying helix formation in the gas phase, in order to fully understand the forces that stabilize the helical structure. In particular, we address the question of whether the local fixation of the positive charge at the peptide's C-terminus is a prerequisite for forming helices by replacing the protonated C-terminal Lys residue by Ala and a sodium cation. The combination of gas-phase vibrational spectroscopy of cryogenically cooled ions with molecular simulations based on density-functional theory (DFT) allows for detailed structure elucidation. For sodiated AcPheAla6, we find globular rather than helical structures, as the mobile positive charge strongly interacts with the peptide backbone and disrupts secondary structure formation. Interestingly, the global minimum structure from simulation is not present in the experiment. We interpret that this is due to high barriers involved in re-arranging the peptide-cation interaction that ultimately result in kinetically trapped structures being observed in the experiment.Comment: 28 pages, 10 figure

Connectivity in real and evolved associative memories

Peer reviewe

Self-stabilizing cluster routing in Manet using link-cluster architecture

We design a self-stabilizing cluster routing algorithm based on the link-cluster architecture of wireless ad hoc networks. The network is divided into clusters. Each cluster has a single special node, called a clusterhead that contains the routing information about inter and intra-cluster communication. A cluster is comprised of all nodes that choose the corresponding clusterhead as their leader. The algorithm consists of two main tasks. First, the set of special nodes (clusterheads) is elected such that it models the link-cluster architecture: any node belongs to a single cluster, it is within two hops of the clusterhead, it knows the direct neighbor on the shortest path towards the clusterhead, and there exist no two adjacent clusterheads. Second, the routing tables are maintained by the clusterheads to store information about nodes both within and outside the cluster. There are two advantages of maintaining routing tables only in the clusterheads. First, as no two neighboring nodes are clusterheads (as per the link-cluster architecture), there is no need to check the consistency of the routing tables. Second, since all other nodes have significantly less work (they only forward messages), they use much less power than the clusterheads. Therefore, if a clusterhead runs out of power, a neighboring node (that is not a clusterhead) can accept the role of a clusterhead. (Abstract shortened by UMI.)