Biophysics-Guided Lead Discovery of HBV Capsid Assembly Modifiers.

Hepatitis B virus (HBV) is the leading cause of chronic liver pathologies worldwide. HBV nucleocapsid, a key structural component, is formed through the self-assembly of the capsid protein units. Therefore, interfering with the self-assembly process is a promising approach for the development of novel antiviral agents. Applied to HBV, this approach has led to several classes of capsid assembly modulators (CAMs). Here, we report structurally novel CAMs with moderate activity and low toxicity, discovered through a biophysics-guided approach combining docking, molecular dynamics simulations, and a series of assays with a particular emphasis on biophysical experiments. Several of the identified compounds induce the formation of aberrant capsids and inhibit HBV DNA replication in vitro, suggesting that they possess modest capsid assembly modulation effects. The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.

Assessing Narrative Microstructure in Mandarin-Speaking School-Age Children.

PURPOSE: As a representative form of discourse, oral narratives offer a sensitive, flexible, and ecologically valid tool for language evaluation. Nevertheless, oral narrative assessments in mainland China remain uncommon among school-age children. Therefore, this study explores the effectiveness of narrative microstructural assessment in Mandarin-speaking school-age children. Its primary purpose is to lay a foundation for future clinical applications by establishing a feasible administration procedure and validating various viable measures to facilitate the evaluation of language proficiencies. METHOD: Narrative samples were collected through a single wordless picture from 285 Mandarin-speaking children ages 7-12 years (Grades 1-6). The samples were then coded using a semiautomatic method for 22 individual measures at word, sentence, and discourse levels. RESULTS: The adapted elicitation method was effective for all grades, with most of the children's stories exhibiting sufficient length, coherent structure, and certain self-fabricated specifics. The semiautomatic coding was also convenient and promising. Altogether, 19 measures were identified as robust predictors of grades, revealing a general tendency of grade-related increase from Grades 1 to 5. These measures exhibited three representative nonlinear trajectory patterns with varied rates of increase. Then, we developed a comprehensive composite measure through factor analysis, which combined six individual measures. The analysis verified the single factor of narrative microstructural competence and showed strong evidence of construct validity. CONCLUSIONS: This study has provided a practical set of administration procedures, validated the efficacy of 19 individual measures as well as a composite measure, and offered corresponding field test data for clinical matching. The findings underscored the reliability and informative nature of oral narrative microstructural assessment in Mandarin-speaking school-age children.

Molecular basis for inhibition of methane clathrate growth by a deep subsurface bacterial protein.

Methane clathrates on continental margins contain the largest stores of hydrocarbons on Earth, yet the role of biomolecules in clathrate formation and stability remains almost completely unknown. Here, we report new methane clathrate-binding proteins (CbpAs) of bacterial origin discovered in metagenomes from gas clathrate-bearing ocean sediments. CbpAs show similar suppression of methane clathrate growth as the commercial gas clathrate inhibitor polyvinylpyrrolidone and inhibit clathrate growth at lower concentrations than antifreeze proteins (AFPs) previously tested. Unlike AFPs, CbpAs are selective for clathrate over ice. CbpA3 adopts a nonglobular, extended structure with an exposed hydrophobic surface, and, unexpectedly, its TxxxAxxxAxx motif common to AFPs is buried and not involved in clathrate binding. Instead, simulations and mutagenesis suggest a bipartite interaction of CbpAs with methane clathrate, with the pyrrolidine ring of a highly conserved proline residue mediating binding by filling empty clathrate cages. The discovery that CbpAs exert such potent control on methane clathrate properties implies that biomolecules from native sediment bacteria may be important for clathrate stability and habitability.

Understanding Virus Structure and Dynamics through Molecular Simulations.

Viral outbreaks remain a serious threat to human and animal populations and motivate the continued development of antiviral drugs and vaccines, which in turn benefits from a detailed understanding of both viral structure and dynamics. While great strides have been made in characterizing these systems experimentally, molecular simulations have proven to be an essential, complementary approach. In this work, we review the contributions of molecular simulations to the understanding of viral structure, functional dynamics, and processes related to the viral life cycle. Approaches ranging from coarse-grained to all-atom representations are discussed, including current efforts at modeling complete viral systems. Overall, this review demonstrates that computational virology plays an essential role in understanding these systems.