Molecular Dynamics Reveal Key Steps in BAR-Related Membrane Remodeling.

Endocytosis plays a complex role in pathogen-host interactions. It serves as a pathway for pathogens to enter the host cell and acts as a part of the immune defense mechanism. Endocytosis involves the formation of lipid membrane vesicles and the reshaping of the cell membrane, a task predominantly managed by proteins containing BAR (Bin1/Amphiphysin/yeast RVS167) domains.

Utilizing AfDesign for Developing a Small Molecule Inhibitor of PICK 1-PDZ.

Introduction: The PICK1 PDZ domain has been identified as a potential drug target for neurological disorders. After many years of effort, a few inhibitors, such as TAT-C5 and mPD5, have been discovered experimentally to bind to the PDZ domain with a relatively high binding affinity. With the rapid growth of computational research, there is an urgent need for more efficient computational methods to design viable ligands that target proteins.

Discriminatory, racist and xenophobic policies and practice against child refugees, asylum seekers and undocumented migrants in European health systems.

Child refugees, asylum seekers and undocumented migrants who have been forcibly displaced from their countries of origin have heightened health needs as a consequence of their migration experiences. Host countries have a duty to respond to these needs, yet across Europe we are seeing a rise in potentially harmful discriminative, hostile and restrictive migration policies and practices. Research exploring the role racism, xenophobia and discrimination in European health systems may play in child migrant health inequities is lacking.

Relational community engagement within health interventions at varied outcome scales.

Relational community engagement may be a powerful approach with multiple health outcomes. Relational community engagement has the potential to promote health and involves collaborative efforts between multiple stakeholders. The COVID-19 pandemic further highlighted the centrality of community engagement in health crises.

Key Factors Regulating the Interdomain Dynamics May Contribute to the Assembly of ASC.

The canonical ASC domains, PYD and CARD, are interconnected by a lengthy, semi-flexible linker. The molecular basis and purpose of ASC's highly dynamic feature remain elusive. In this study, all-atom molecular dynamics simulations were utilized to examine the role of the linker and the interdomain dynamics of the ASC monomer.

Investigating the Mechanical Properties and Flexibility of N-BAR Domains in PICK1 by Molecular Dynamics Simulations.

Introduction: The proteins of the Bin/Amphiphysin/Rvs167 (BAR) domain superfamily are believed to induce membrane curvature. PICK1 is a distinctive protein that consists of both a BAR and a PDZ domain, and it has been associated with numerous diseases. It is known to facilitate membrane curvature during receptor-mediated endocytosis.

Emulsion-induced polymersomes taming tetrodotoxin for prolonged duration local anesthesia.

Injectable local anesthetics that can provide a continuous nerve block approximating the duration of a pain state would be a life-changing solution for patients experiencing post-operative pain or chronic pain. Tetrodotoxin (TTX) is a site 1 sodium channel blocker that is extremely potent compared to clinically used local anesthetics. Challengingly, TTX doses are limited by its associated systemic toxicity, thus shortening the achievable duration of nerve blocks.

Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all-atom simulations.

The PDZ family is comprised of small modular domains that play critical roles in the allosteric modulation of many cellular signaling processes by binding to the C-terminal tail of different proteins. As dominant modular proteins that interact with a diverse set of peptides, it is of particular interest to explore how different binding partners induce different allosteric effects on the same PDZ domain. Because the PICK1 PDZ domain can bind different types of ligands, it is an ideal test case to answer this question and explore the network of interactions that give rise to dynamic allostery.

Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex.

The dynamic association and dissociation between proteins are the basis of cellular signal transduction. This process becomes much more complicated if one or both interaction partners are intrinsically disordered because intrinsically disordered proteins can undergo disorder-to-order transitions upon binding to their partners. p53, a transcription factor with disordered regions, plays significant roles in many cellular signaling pathways.

Three Binding Conformations of BIO124 in the Pocket of the PICK1 PDZ Domain.

The PDZ family has drawn attention as possible drug targets because of the domains' wide ranges of function and highly conserved binding pockets. The PICK1 PDZ domain has been proposed as a possible drug target because the interactions between the PICK1 PDZ domain and the GluA2 subunit of the AMPA receptor have been shown to progress neurodegenerative diseases. BIO124 has been identified as a sub µM inhibitor of the PICK1-GluA2 interaction.

Benchmarking the Accuracy of AlphaFold 2 in Loop Structure Prediction.

The inhibition of protein-protein interactions is a growing strategy in drug development. In addition to structured regions, many protein loop regions are involved in protein-protein interactions and thus have been identified as potential drug targets. To effectively target such regions, protein structure is critical.

Allosterism in the PDZ Family.

Dynamic allosterism allows the propagation of signal throughout a protein. The PDZ (PSD-95/Dlg1/ZO-1) family has been named as a classic example of dynamic allostery in small modular domains. While the PDZ family consists of more than 200 domains, previous efforts have primarily focused on a few well-studied PDZ domains, including PTP-BL PDZ2, PSD-95 PDZ3, and Par6 PDZ.

Correlates of solitary alcohol and cannabis use among American Indian adolescents.

Background: Solitary substance use, or using substances while alone, is common among adolescents but understudied. This is the first study to examine solitary substance use among American Indian (AI) adolescents. The objective was to examine correlates of solitary alcohol use and solitary cannabis use that occur within the individual, family, school, peer, and cultural domains of the social ecology.

The experiences of socially vulnerable groups in England during the COVID-19 pandemic: A rapid health needs assessment.

Objectives: This rapid health needs assessment was undertaken to urgently identify the needs of socially vulnerable groups arising during the first wave of cases of the COVID-19 pandemic in England. The objective was to develop recommendations for policy makers and stakeholders to mitigate adverse impacts on socially vulnerable groups throughout the COVID-19 response and recovery period.

Study Design: Rapid health needs assessment.

Associations of childhood executive control with adolescent cigarette and E-cigarette use: Tests of moderation by poverty level.

Background: Adolescent cigarette smoking has continued to decline, whereas electronic cigarette (e-cigarette) use has increased dramatically among youth. Nicotine use in any form, even at low levels, during adolescence can have adverse consequences, particularly for low-income individuals. To elucidate potential early intervention targets, this study examined childhood executive control (EC), a set of cognitive processes for directing attention and behavior, in relation to adolescent cigarette and e-cigarette onset, testing for differential prediction by poverty level.

Residue-Level Contact Reveals Modular Domain Interactions of PICK1 Are Driven by Both Electrostatic and Hydrophobic Forces.

PICK1 is a multi-domain scaffolding protein that is uniquely comprised of both a PDZ domain and a BAR domain. While previous experiments have shown that the PDZ domain and the linker positively regulate the BAR domain and the C-terminus negatively regulates the BAR domain, the details of internal regulation mechanisms are unknown. Molecular dynamics (MD) simulations have been proven to be a useful tool in revealing the intramolecular interactions at atomic-level resolution.