Predicting the impact of new emerging virus mutations is of major interest in surveillance and for understanding the evolutionary forces of the pathogens. The SARS-CoV-2 surface spike-protein (S-protein) binds to human ACE2 receptors as a critical step in host cell infection. At the same time, S-protein binding to human antibodies neutralizes the virus and prevents interaction with ACE2.
View Article and Find Full Text PDFThe binding affinity of the SARS-CoV-2 spike (S)-protein to the human membrane protein ACE2 is critical for virus function. Computational structure-based screening of new S-protein mutations for ACE2 binding lends promise to rationalize virus function directly from protein structure and ideally aid early detection of potentially concerning variants. We used a computational protocol based on cryo-electron microscopy structures of the S-protein to estimate the change in ACE2-affinity due to S-protein mutation (ΔΔG) in good trend agreement with experimental ACE2 affinities.
View Article and Find Full Text PDFAmyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) are neurodegenerations with evolutionary underpinnings, expansive clinical presentations, and multiple genetic risk factors involving a complex network of pathways. This perspective considers the complex cellular pathology of aging motoneuronal and frontal/prefrontal cortical networks in the context of evolutionary, clinical, and biochemical features of the disease. We emphasize the importance of evolution in the development of the higher cortical function, within the influence of increasing lifespan.
View Article and Find Full Text PDFZinc is well-known to have a central role in human inflammation and immunity and is itself an anti-inflammatory and antiviral agent. Despite its massively documented role in such processes, the underlying chemistry of zinc in relation to specific proteins and pathways of the immune system has not received much focus. This short review provides an overview of this topic, with emphasis on the structures of key proteins, zinc coordination chemistry, and probable mechanisms involved in zinc-based immunity, with some focus points for future chemical and biological research.
View Article and Find Full Text PDFThe inability to effectively halt or cure Alzheimer's disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated. These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.
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