Aided by efforts to improve their speed and efficiency, molecular dynamics (MD) simulations provide an increasingly powerful tool to study the structure–function relationship of pentameric ligand-gated ion channels (pLGICs). However, accurate reporting of the channel state and observation of allosteric regulation by agonist binding with MD remains difficult due to the timescales necessary to equilibrate pLGICs from their artificial and crystalized conformation to a more native, membrane-bound conformation in silico. Here, we perform multiple all-atom MD simulations of the homomeric 5-hydroxytryptamine 3A (5-HT3A) serotonin receptor for 15 to 20 μs to demonstrate that such timescales are critical to observe the equilibration of a pLGIC from its crystalized conformation to a membrane-bound conformation. These timescales, which are an order of magnitude longer than any previous simulation of 5-HT3A, allow us to observe the dynamic binding and unbinding of 5-hydroxytryptamine (5-HT) (i.e., serotonin) to the binding pocket located on the extracellular domain (ECD) and allosteric regulation of the transmembrane domain (TMD) from synergistic 5-HT binding. While these timescales are not long enough to observe complete activation of 5-HT3A, the allosteric regulation of ion gating elements by 5-HT binding is indicative of a preactive state, which provides insight into molecular mechanisms that regulate channel activation from a resting state. This mechanistic insight, enabled by microsecond-timescale MD simulations, will allow a careful examination of the regulation of pLGICs at a molecular level, expanding our understanding of their function and elucidating key structural motifs that can be targeted for therapeutic regulation.

Metal-mediated exfoliation has been demonstrated as a promising approach for obtaining largearea flakes of 2D materials to fabricate prototypical nanoelectronics. However, several processing challenges related to organic contamination at the interfaces of the 2D material and the gate oxide must be overcome to realize robust devices with high yield. Here, we demonstrate an optimized process to realize high-performance field-effect transistor (FET) arrays from largearea (» 5000 μm 2 ) monolayer MoS2 with a yield of 85 %. A central element of this process is an exposed material forming gas anneal (EM-FGA) that results in uniform FET performance metrics (i.e., field-effect mobilities, threshold voltages, and contact performance). Complementary analytical measurements show that the EM-FGA process reduces deleterious channel doping effects by decreasing organic contamination, while also reducing the prevalence of insulating molybdenum oxide, effectively improving the MoS2-gate oxide interface. The uniform FET performance metrics and high device yield achieved by applying the EM-FGA technique on large-area 2D material flakes will help advance the fabrication of complex 2D nanoelectronics devices and demonstrates the need for improved engineering of the 2D materialgate oxide interface.

We have demonstrated atomically thin, quantum capacitance-limited, field-effect transistors (FETs) that enable the detection of pH changes with »75-fold higher sensitivity (4.4 V/pH) over the Nernst value of 59 mV/pH at room temperature when used as a biosensor. The transistors, which are fabricated from a monolayer of MoS2 with a room temperature ionic liquid (RTIL) in place of a conventional oxide gate dielectric, exhibit very low intrinsic noise resulting in a pH limit of detection (LOD) of 92´10 -6 at 10 Hz. This high device performance, which is a function of the structure of our device, is achieved by remotely connecting the gate to a pH sensing element allowing the FETs to be reused. Because pH measurements are fundamentally important in biotechnology, the low limit of detection demonstrated here will benefit numerous applications ranging from pharmaceutical manufacturing to clinical diagnostics. As an example, we experimentally quantified the function of the kinase Cdk5, an enzyme implicated in Alzheimer's disease, at concentrations that are 5-fold lower than physiological values, and with sufficient time-resolution to allow the estimation of both steady-state and kinetic parameters in a single experiment. The high sensitivity, low LOD and fast turnaround time of the measurements will allow the development of early diagnostic tools and novel therapeutics to detect and treat neurological conditions years before currently possible. Keywords:Field-effect transistor (FET), Room temperature ionic liquid (RTIL), MoS2, Biosensor, Super-Nernstian, pH, Enzyme activity, Enzyme kinetics.Rapid and sensitive pH measurements based on field-effect transistors (FETs) are used in diverse applications that include determining the effects of ocean acidification on marine ecology, 1 biomanufacturing, 2 and low cost DNA sequencers. 3 However, drastic improvements in sensitivity and the limit of detection (LOD) of electronic pH transduction are needed to accelerate their widespread use in important biotechnology applications. One such example is the