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 a kink in the monomer between two helical fragments having 20 degrees and 31 degrees tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric amantadine-blocked M2 trans-membrane channel. The influence of amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the amantadine-resistant mutant, S31N, in the presence and absence of amantadine.

Networks of model neurons were constructed and their activity was predicted using an iterated map based solely on the phase-resetting curves (PRCs). The predictions were quite accurate provided that the resetting to simultaneous inputs was calculated using the sum of the simultaneously active conductances, obviating the need for weak coupling assumptions. Fully synchronous activity was observed only when the slope of the PRC at a phase of zero, corresponding to spike initiation, was positive. A novel stability criterion was developed and tested for all-to-all networks of identical, identically connected neurons. When the PRC generated using N Ϫ 1 simultaneously active inputs becomes too steep, the fully synchronous mode loses stability in a network of N model neurons. Therefore, the stability of synchrony can be lost by increasing the slope of this PRC either by increasing the network size or the strength of the individual synapses. Existence and stability criteria were also developed and tested for the splay mode in which neurons fire sequentially. Finally, N/M synchronous subclusters of M neurons were predicted using the intersection of parameters that supported both between-cluster splay and within-cluster synchrony. Surprisingly, the splay mode between clusters could enforce synchrony on subclusters that were incapable of synchronizing themselves. These results can be used to gain insights into the activity of networks of biological neurons whose PRCs can be measured.

Limit cycle oscillators that are coupled in a pulsatile manner are referred to as pulse coupled oscillators. In these oscillators, the interactions take the form of brief pulses such that the effect of one input dies out before the next is received. A phase resetting curve (PRC) keeps track of how much an input advances or delays the next spike in an oscillatory neuron depending upon where in the cycle the input is applied. PRCs can be used to predict phase locking in networks of pulse coupled oscillators. In some studies of pulse coupled oscillators, a specific form is assumed for the interactions between oscillators, but a more general approach is to formulate the problem assuming a PRC that is generated using a perturbation that approximates the input received in the real biological network. In general, this approach requires that circuit architecture and a specific firing pattern be assumed. This allows the construction of discrete maps from one event to the next. The fixed points of these maps correspond to periodic firing modes and are easier to locate and analyze for stability compared to locating and analyzing periodic modes in the original network directly. Alternatively, maps based on the PRC have been constructed that do not presuppose a firing order. Specific circuits that have been analyzed under the assumption of pulsatile coupling include one to one lockings in a periodically forced oscillator or an oscillator forced at a fixed delay after a threshold event, two bidirectionally coupled oscillators with and without delays, a unidirectional N-ring of oscillators, and N all-to-all networks.

Despite the wealth of knowledge gained about intrinsically disordered proteins (IDPs) since their discovery, there are several aspects that remain unexplored and, hence, poorly understood. A living cell is a complex adaptive system that can be described as a wetwarea metaphor used to describe the cell as a computer comprising both hardware and software and attuned to logic gatescapable of “making” decisions. In this focused Review, we discuss how IDPs, as critical components of the wetware, influence cell-fate decisions by wiring protein interaction networks to keep them minimally frustrated. Because IDPs lie between order and chaos, we explore the possibility that they can be modeled as attractors. Further, we discuss how the conformational dynamics of IDPs manifests itself as conformational noise, which can potentially amplify transcriptional noise to stochastically switch cellular phenotypes. Finally, we explore the potential role of IDPs in prebiotic evolution, in forming proteinaceous membrane-less organelles, in the origin of multicellularity, and in protein conformation-based transgenerational inheritance of acquired characteristics. Together, these ideas provide a new conceptual framework to discern how IDPs may perform critical biological functions despite their lack of structure.

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