Balancing G protein selectivity and efficacy in the adenosine A receptor.

The adenosine A receptor (AR) engages several G proteins, notably G and its cognate G protein. This coupling promiscuity is facilitated by a dynamic ensemble, revealed by F nuclear magnetic resonance imaging of AR and G protein. Two transmembrane helix 6 (TM6) activation states, formerly associated with partial and full agonism, accommodate the differing volumes of G and G.

PaCS-Toolkit: Optimized Software Utilities for Parallel Cascade Selection Molecular Dynamics (PaCS-MD) Simulations and Subsequent Analyses.

Parallel cascade selection molecular dynamics (PaCS-MD) is an enhanced conformational sampling method conducted as a "repetition of time leaps in parallel worlds", comprising cycles of multiple molecular dynamics (MD) simulations performed in parallel and selection of the initial structures of MDs for the next cycle. We developed PaCS-Toolkit, an optimized software utility enabling the use of different MD software and trajectory analysis tools to facilitate the execution of the PaCS-MD simulation and analyze the obtained trajectories, including the preparation for the subsequent construction of the Markov state model. PaCS-Toolkit is coded with Python, is compatible with various computing environments, and allows for easy customization by editing the configuration file and specifying the MD software and analysis tools to be used.

Engineering of an in-cell protein crystal for fastening a metastable conformation of a target miniprotein.

Protein crystals can be utilized as porous scaffolds to capture exogenous molecules. Immobilization of target proteins using protein crystals is expected to facilitate X-ray structure analysis of proteins that are difficult to be crystallized. One of the advantages of scaffold-assisted structure determination is the analysis of metastable structures that are not observed in solution.

Metal-Oxide FET Biosensor for Point-of-Care Testing: Overview and Perspective.

Metal-oxide semiconducting materials are promising for building high-performance field-effect transistor (FET) based biochemical sensors. The existence of well-established top-down scalable manufacturing processes enables the reliable production of cost-effective yet high-performance sensors, two key considerations toward the translation of such devices in real-life applications. Metal-oxide semiconductor FET biochemical sensors are especially well-suited to the development of Point-of-Care testing (PoCT) devices, as illustrated by the rapidly growing body of reports in the field.

Structure of MotA, a flagellar stator protein, from hyperthermophile.

Many motile bacteria swim and swarm toward favorable environments using the flagellum, which is rotated by a motor embedded in the inner membrane. The motor is composed of the rotor and the stator, and the motor torque is generated by the change of the interaction between the rotor and the stator induced by the ion flow through the stator. A stator unit consists of two types of membrane proteins termed A and B.

Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer.

Non-structural protein 15 (Nsp15) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) forms a homo hexamer and functions as an endoribonuclease. Here, we propose that Nsp15 activity may be inhibited by preventing its hexamerization through drug binding. We first explored the stable conformation of the Nsp15 monomer as the global free energy minimum conformation in the free energy landscape using a combination of parallel cascade selection molecular dynamics (PaCS-MD) and the Markov state model (MSM), and found that the Nsp15 monomer forms a more open conformation with larger druggable pockets on the surface.

Integrated Platform Addressing the Finger-Prick Blood Processing Challenges of Point-of-Care Electrical Biomarker Testing.

Continued advances in label-free electrical biosensors pave the way to simple, rapid, cost-effective, high-sensitivity, and quantitative biomarker testing at the point-of-care setting that would profoundly transform healthcare. However, implementation in routine diagnostics is faced with significant challenges associated with the inherent requirement for biofluid sample processing before and during testing. We present here a simple yet robust autonomous finger-prick blood sample processing platform integrated with nanoscale field-effect transistor biosensors and demonstrate the feasibility of measuring the SARS-CoV-2 nucleocapsid protein.

Evaluating Discrepancies in Percent Total Body Surface Area Burn Assessments Between Prehospital Providers and Burn Center Physicians.

Burns are routinely assessed at the scene of the incident by prehospital or emergency medical services providers. The initial management of burns is based on the calculation of the extent of the injury, reported as percent total body surface area (TBSA). This study evaluates discrepancies in the estimation of TBSA between prehospital providers and burn team physicians over a 3-year period at an academic, university medical center serving as the regional burn center.

A simplified point-of-care testing approach for preeclampsia blood biomarkers based on nanoscale field effect transistors.

Rapid diagnosis of preeclampsia is necessary to ensure timely administration of appropriate care and prevent the potentially catastrophic complications of the condition affecting both mothers and babies. While the diagnostic superiority of angiogenic blood biomarkers such as placental growth factor has recently been demonstrated, there is an urgent need to develop point-of-care (PoC) technologies that allow rapid, quantitative, and accurate testing for these markers within local communities. Towards addressing this need, here we report on a fully integrated biodiagnostic platform based on nanoscale indium oxide field effect transistor (FET) sensors.

Using molecular dynamics simulations to prioritize and understand AI-generated cell penetrating peptides.

Cell-penetrating peptides have important therapeutic applications in drug delivery, but the variety of known cell-penetrating peptides is still limited. With a promise to accelerate peptide development, artificial intelligence (AI) techniques including deep generative models are currently in spotlight. Scientists, however, are often overwhelmed by an excessive number of unannotated sequences generated by AI and find it difficult to obtain insights to prioritize them for experimental validation.

Delineating the conformational landscape of the adenosine A receptor during G protein coupling.

G-protein-coupled receptors (GPCRs) represent a ubiquitous membrane protein family and are important drug targets. Their diverse signaling pathways are driven by complex pharmacology arising from a conformational ensemble rarely captured by structural methods. Here, fluorine nuclear magnetic resonance spectroscopy (F NMR) is used to delineate key functional states of the adenosine A receptor (AR) complexed with heterotrimeric G protein (Gαβγ) in a phospholipid membrane milieu.

Bilateral Acute Angle Closure in a Pediatric Patient Taking Lisdexamfetamine Dimesylate (Vyvanse).

Attention-deficit/hyperactivity disorder is commonly treated with amphetamines as first line therapy. Rare case reports have shown amphetamines are associated with open angle glaucoma. We report a rare case of a 14-year-old male who presented with bilateral acute angle closure presumed to be related to his use of lisdexamfetamine dimesylate (Vyvanse).

Generating Ampicillin-Level Antimicrobial Peptides with Activity-Aware Generative Adversarial Networks.

Antimicrobial peptides are a potential solution to the threat of multidrug-resistant bacterial pathogens. Recently, deep generative models including generative adversarial networks (GANs) have been shown to be capable of designing new antimicrobial peptides. Intuitively, a GAN controls the probability distribution of generated sequences to cover active peptides as much as possible.

Edge expansion parallel cascade selection molecular dynamics simulation for investigating large-amplitude collective motions of proteins.

We propose edge expansion parallel cascade selection molecular dynamics (eePaCS-MD) as an efficient adaptive conformational sampling method to investigate the large-amplitude motions of proteins without prior knowledge of the conformational transitions. In this method, multiple independent MD simulations are iteratively conducted from initial structures randomly selected from the vertices of a multi-dimensional principal component subspace. This subspace is defined by an ensemble of protein conformations sampled during previous cycles of eePaCS-MD.

Kinetic Selection and Relaxation of the Intrinsically Disordered Region of a Protein upon Binding.

Here, we investigate the association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor suppressor protein p53 (TAD-p53), with murine double-minute clone 2 protein (MDM2). Using a combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard molecular dynamics (MD), and the Markov state model, we were successful in obtaining the lowest free energy structure of the MDM2/TAD-p53 complex as the structure closest to the crystal structure without prior knowledge of the crystal structure. This method also reproduced the experimentally measured standard binding free energy, and the association and dissociation rate constants, requiring only an accumulated MD simulation cost of 11.

Electronic and optical properties of Janus ZrSSe by density functional theory.

In the present work, we investigate systematically the electronic and optical properties of Janus ZrSSe using first-principles calculations. Our calculations demonstrate that the Janus ZrSSe monolayer is an indirect semiconductor at equilibrium. The band gap of the Janus ZrSSe is 1.

High performance indium oxide nanoribbon FETs: mitigating devices signal variation from batch fabrication.

Nanostructured field effect transistor (FET) based sensors have emerged as a powerful bioanalytical technology. However, performance variations across multiple devices and between fabrication batches inevitably exist and present a significant challenge holding back the translation of this cutting-edge technology. We report an optimized and cost-effective fabrication process for high-performance indium oxide nanoribbon FET with a steep subthreshold swing of 80 mV per decade.

Silicon Nanowires Field Effect Transistors: A Comparative Sensing Performance between Electrical Impedance and Potentiometric Measurement Paradigms.

Potentiometric sensors based on silicon nanowire field effect transistors (SiNW FETs) typically display exquisite sensitivities, but their bioanalytical implementation is limited due to the need for stringent measurement conditions and high-precision readout units. An alternative operation principle where SiNW FETs are operated in a frequency-domain electrical impedimetric approach is promising. However, to date only limited data is available in regard to the sensing performance and translational relevance of this novel approach in comparison to the standard charge detection paradigm.

Surface Plasmon Enhanced Light Scattering Biosensing: Size Dependence on the Gold Nanoparticle Tag.

Surface plasmon enhanced light scattering (SP-LS) is a powerful new sensing SPR modality that yields excellent sensitivity in sandwich immunoassay using spherical gold nanoparticle (AuNP) tags. Towards further improving the performance of SP-LS, we systematically investigated the AuNP size effect. Simulation results indicated an AuNP size-dependent scattered power, and predicted the optimized AuNPs sizes (i.

Dissociation Process of a MDM2/p53 Complex Investigated by Parallel Cascade Selection Molecular Dynamics and the Markov State Model.

Recently, we efficiently generated dissociation pathways of a protein-ligand complex without applying force bias with parallel cascade selection molecular dynamics (PaCS-MD) and showed that PaCS-MD in combination with the Markov state model (MSM) yielded a binding free energy comparable to experimental values. In this work, we applied the same procedure to a complex of MDM2 protein and the transactivation domain of p53 protein (TAD-p53), the latter of which is known to be very flexible in the unbound state. Using 30 independent MD simulations in PaCS-MD, we successfully generated 25 dissociation pathways of the complex, which showed complete or partial unfolding of the helical region of TAD-p53 during the dissociation process within an average simulation time of 154.

In silico study of Bombyx mori fibroin enhancement by graphene in acidic environment.

Bombyx mori fibroin has been widely used since a long time ago and has become a popular material. Here, we carry out a molecular dynamics simulation-based docking simulation of a small fragment of graphene in order to seek the best binding position on the N-termini domain of Bombyx mori fibroin. We report the best binding position, of which binding free energy falls at -54.

CMOS-Compatible Silicon Nanowire Field-Effect Transistor Biosensor: Technology Development toward Commercialization.

Owing to their two-dimensional confinements, silicon nanowires display remarkable optical, magnetic, and electronic properties. Of special interest has been the development of advanced biosensing approaches based on the field effect associated with silicon nanowires (SiNWs). Recent advancements in top-down fabrication technologies have paved the way to large scale production of high density and quality arrays of SiNW field effect transistor (FETs), a critical step towards their integration in real-life biosensing applications.