Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics.

Grp94, an ER-localized molecular chaperone, is required for the folding and activation of many membrane and secretory proteins. Client activation by Grp94 is mediated by nucleotide and conformational changes. In this work, we aim to understand how microscopic changes from nucleotide hydrolysis can potentiate large-scale conformational changes of Grp94. We performed all-atom molecular dynamics simulations on the ATP-hydrolysis competent state of the Grp94 dimer in four different nucleotide bound states. We found that Grp94 was the most rigid when ATP was bound. ATP hydrolysis or nucleotide removal enhanced mobility of the N-terminal domain and ATP lid, resulting in suppression of interdomain communication. In an asymmetric conformation with one hydrolyzed nucleotide, we identified a more compact state, similar to experimental observations. We also identified a potential regulatory role of the flexible linker, as it formed electrostatic interactions with the Grp94 M-domain helix near the region where BiP is known to bind. These studies were complemented with normal-mode analysis of an elastic network model to investigate Grp94's large-scale conformational changes. SPM analysis identified residues that are important in signaling conformational change, many of which have known functional relevance in ATP coordination and catalysis, client binding, and BiP binding. Our findings suggest that ATP hydrolysis in Grp94 alters allosteric wiring and facilitates conformational changes.

The Technological Impact of COVID-19 on the Future of Education and Health Care Delivery.

BACKGROUND: The unexpected COVID-19 crisis has disrupted medical education and patient care in unprecedented ways. Despite the challenges, the health-care system and patients have been both creative and resilient in finding robust "temporary" solutions to these challenges. It is not clear if some of these COVID-era transitional steps will be preserved in the future of medical education and telemedicine. OBJECTIVES: The goal of this commentary is to address the sometimes substantial changes in medical education, continuing medical education (CME) activities, residency and fellowship programs, specialty society meetings, and telemedicine, and to consider the value of some of these profound shifts to "business as usual" in the health-care sector. METHODS: This is a commentary is based on the limited available literature, online information, and the front-line experiences of the authors. RESULTS: COVID-19 has clearly changed residency and fellowship programs by limiting the amount of hands-on time physicians could spend with patients. Accreditation Council for Graduate Medicine Education has endorsed certain policy changes to promote greater flexibility in programs but still rigorously upholds specific standards. Technological interventions such as telemedicine visits with patients, virtual meetings with colleagues, and online interviews have been introduced, and many trainees are "techno-omnivores" who are comfortable using a variety of technology platforms and techniques. Webinars and e-learning are gaining traction now, and their use, practicality, and cost-effectiveness may make them important in the post-COVID era. CME activities have migrated increasingly to virtual events and online programs, a trend that may also continue due to its practicality and cost-effectiveness. While many medical meetings of specialty societies have been postponed or cancelled altogether, technology allows for virtual meetings that may offer versatility and time-saving opportunities for busy clinicians. It may be that future medical meetings embrace a hybrid approach of blending digital with face-to-face experience. Telemedicine was already in place prior to the COVID-19 crisis but barriers are rapidly coming down to its widespread use and patients seem to embrace this, even as health-care systems navigate the complicated issues of cybersecurity and patient privacy. Regulatory guidance may be needed to develop safe, secure, and patient-friendly telehealth applications. Telemedicine has affected the prescribing of controlled substances in which online counseling, informed consent, and follow-up must be done in a virtual setting. For example, pill counts can be done in a video call and patients can still get questions answered about their pain therapy, although it is likely that after the crisis, prescribing controlled substances may revert to face-to-face visits. LIMITATIONS: The health-care system finds itself in a very fluid situation at the time this was written and changes are still occurring and being assessed. CONCLUSIONS: Many of the technological changes imposed so abruptly on the health-care system by the COVID-19 pandemic may be positive and it may be beneficial that some of these transitions be preserved or modified as we move forward. Clinicians must be objective in assessing these changes and retaining those changes that clearly improve health-care education and patient care as we enter the COVID era.