Allosteric Regulation of SARS-CoV-2 Protease: Towards Informed Structure-Based Drug Discovery

The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 ± 1.9 kJ/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.

Allosteric Regulation of SARS-CoV-2 Protease: Towards Informed Structure-Based Drug Discovery

The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 ± 1.9 kJ/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.

Allosteric Regulation of SARS-CoV-2 Protease: Towards Informed Structure-Based Drug Discovery

The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 ± 1.9 kJ/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.

FUTURE SOCIAL WORKER TRAINING IN FACILITATION INTERACTION WITH PEOPLE OF DIFFERENT AGES AND SOCIAL STATUS

The article describes the peculiarities of future social worker training in facilitation interaction with people of different ages and social status; it is shown how the technologies of ‘dyad interaction’ and future specialists in social work situational training are applied on the basis of facilitation; an analysis of their implementation in the practice of future social worker training in facilitation interaction with people of different ages and social status is given. The aim of the paper is to summarize the practical work of researchers from English-speaking countries on the effective use of postclassical didactics (‘dyad interaction’ and situational learning) in the practice of social worker training in facilitation interaction with people of different ages and social status. The essence of ‘case-method technology implementation in the practice of future social worker training in facilitation interaction with people of different ages and social status is contained; it is contained in a change of the purpose of training (awareness that there is a possibility of many solutions in social and social-pedagogical work of; democratic nature of the process of acquiring knowledge, equality with other participants, in particular with the lecturer, when the main thing is to develop in the process of co-creation of the future specialist in social work with the lecturer new knowledge, skills of facilitation interaction with people of different ages and social status; the method on the basis of which the system of values of future specialists in social work as facilitators develops, their facilitation positions, life attitudes, a kind of professional worldview, etc. are formed). A description of the functional forms and qualities of dyad interaction is presented. Considering the relative compactness and simplicity, they are used by lecturers in the process of future social worker training in facilitation interaction with people of different ages and social status. It has improved the quality of the lecturer’s dyad interaction with future social workers.

Building Emotional Intelligence for Student Success: A Pilot Study

Purpose Nationwide, upward trends exist in student issues with anxiety, stress, depression, and lowered classroom performance. As emotional awareness and emotional regulation skills are typically not addressed in professional discipline-specific courses, students experience challenges in their academic performance. This pilot research explored the effect of brief targeted classroom practices within an empowerment-based framework on domains of emotional intelligence. Method Twenty-two students in an undergraduate speech-language pathology class received a 13-week, biweekly, 15-min session of empowerment-based worksheet exercises to develop increased self-esteem, emotional awareness and regulation, and communication. Assessments of self-esteem, emotional intelligence, communication competence, and communication apprehension were conducted using validated scales, namely, the Rosenberg Self-Esteem Scale ( Rosenberg, 1965 ), the Quick Emotional Intelligence Self-Assessment ( Mohapel, 2015 ), the Self-Perceived Communication Competence Scale ( McCroskey & McCroskey, 2013 ), and the Personal Report of Communication Apprehension ( McCroskey, 1982 ), respectively. Midsemester and semester-end student reflections were collected. Results Paired t tests were significant in self-esteem and emotional quotient, including subdomains of emotional awareness, emotional management, social emotional awareness, and relational management. Significance was noted in communication competence in the subdomains of dyad interaction, stranger interaction, and acquaintance. Students' reflection showed significant improvement in empowerment and self-rated improvements in confidence, communication, connections with peers, and trust with instructor. Conclusion Preliminary evidence demonstrates positive outcomes with integration of intentional classroom exercises to build emotional intelligence (including emotional awareness and regulation), self-esteem, and communication. This empowerment model may assist faculty in developing effective pedagogical strategies to build students' self-resiliency.

Identifying and measuring network-based relational uncertainty: Looking outside of the dyadic bubble

Previous research has explored both relational uncertainty and the importance of partners’ social networks in the development of close relationships. Combining these concepts would better facilitate our understanding of relational development. Accordingly, this four-study identifies and creates a novel measure for social network-based relational uncertainty experienced by individuals in romantic relationships. Studies 1 and 2 reveal eight distinct categories of network uncertainty via open coding. Studies 3 and 4 use these categories to create a network uncertainty measure (NUM) and compare it to several scales from relational turbulence theory. Exploratory and confirmatory factor analysis revealed five subscales, which derived from the original eight categories. Tests of convergent and divergent validity validate the NUM as a viable measure to be used in theory expansion as well as studies of network-dyad interaction. Regression analyses first compared the NUM to measures of self, partner, and relationship uncertainty. Results demonstrated strong empirical relationships between these variables, reaffirming conceptual similarities. Moreover, measures of relationship satisfaction intimacy were regressed on the NUM, controlling for relational uncertainty measures. Results demonstrated that the NUM contributes to these outcomes above and beyond self, partner, and relationship uncertainty. Findings are discussed in terms of empirical and conceptual value to the study of romantic relationships.