Physical Sciences and Mathematics Commons^™

Apigenin Alleviates Autistic-Like Stereotyped Repetitive Behaviors And Mitigates Brain Oxidative Stress In Mice, Petrilla Jayaprakash, Dmytro Isaev, Keun-Hang Susan Yang, Rami Beiram, Murat Oz, Bassem Sadek

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10–30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 …

Climate Change-Associated Declines In Water Clarity Impair Feeding By Common Loons, Walter H. Piper, Max R. Glines, Kevin C. Rose

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Climate change has myriad impacts on ecosystems, but the mechanisms by which it affects individual species can be difficult to pinpoint. One strategy to discover such mechanisms is to identify a specific ecological factor related to survival or reproduction and determine how that factor is affected by climate. Here we used Landsat imagery to calculate water clarity for 127 lakes in northern Wisconsin from 1995 to 2021 and thus investigate the effect of clarity on the body condition of an aquatic visual predator, the common loon (Gavia immer). In addition, we examined rainfall and temperature as potential predictors …

Methionyl-Trna Synthetase Synthetic And Proofreading Activities Are Determinants Of Antibiotic Persistence, Whitney N. Wood, Miguel Angel Rubio, Lorenzo Eugenio Leiva, Gregory J. Phillips, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Bacterial antibiotic persistence is a phenomenon where bacteria are exposed to an antibiotic and the majority of the population dies while a small subset enters a low metabolic, persistent, state and are able to survive. Once the antibiotic is removed the persistent population can resuscitate and continue growing. Several different molecular mechanisms and pathways have been implicated in this phenomenon. A common mechanism that may underly bacterial antibiotic persistence is perturbations in protein synthesis. To investigate this mechanism, we characterized four distinct metG mutants for their ability to increase antibiotic persistence. Two metG mutants encode changes near the catalytic site …

Β-Sheets Mediate The Conformational Change And Allosteric Signal Transmission Between The Aslov2 Termini, Sian Xiao, Mayar Terek Ibrahim, Gennady M. Verkhivker, Brian D. Zoltowski, Peng Tao

Mathematics, Physics, and Computer Science Faculty Articles and Research

Avena sativa phototropin 1 light-oxygen-voltage 2 domain (AsLOV2) is a model protein of Per-Arnt-Sim (PAS) superfamily, characterized by conformational changes in response to external environmental stimuli. This conformational change begins with the unfolding of the N-terminal A'α helix in the dark state followed by the unfolding of the C-terminal Jα helix. The light state is characterized by the unfolded termini and the subsequent modifications in hydrogen bond patterns. In this photoreceptor, β-sheets are identified as crucial components for mediating allosteric signal transmission between the two termini. Through combined experimental and computational investigations, the Hβ …

Toward A Coordinated Understanding Of Hydro-Biogeochemical Root Functions In Tropical Forests For Application In Vegetation Models, Daniela F. Cusack, Bradley Christoffersen, Chris M. Smith-Martin, Kelly M. Andersen, Amanda L. Cordeiro, Katrin Fleischer, S. Joseph Wright, Nathaly R. Guerrero-Ramírez, Laynara F. Lugli, Lindsay A. Mcculloch, Mareli Sanchez-Julia, Sarah A. Batterman, Caroline Dallstream, Claire Fortunel, Laura Toro, Lucia Fuchslueger, Michelle Y. Wong, Daniela Yaffar, Joshua B. Fisher, Marie Arnaud, Lee H. Dietterich, Shalom D. Addo-Danso, Oscar J. Valverde-Barrantes, Monique Weemstra, Jing Cheng Ng, Richard J. Norby

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Tropical forest root characteristics and resource acquisition strategies are underrepresented in vegetation and global models, hampering the prediction of forest–climate feedbacks for these carbon-rich ecosystems. Lowland tropical forests often have globally unique combinations of high taxonomic and functional biodiversity, rainfall seasonality, and strongly weathered infertile soils, giving rise to distinct patterns in root traits and functions compared with higher latitude ecosystems. We provide a roadmap for integrating recent advances in our understanding of tropical forest belowground function into vegetation models, focusing on water and nutrient acquisition. We offer comparisons of recent advances in empirical and model understanding of root characteristics …

Mutational Analysis Of The Nitrogenase Carbon Monoxide Protective Protein Cown Reveals That A Conserved C‑Terminal Glutamic Acid Residue Is Necessary For Its Activity, Dustin L. Willard, Joshuah J. Arellano, Mitch Underdahl, Terrence M. Lee, Avinash S. Ramaswamy, Gabriella Fumes, Agatha Kliman, Emily Y. Wong, Cedric P. Owens

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Nitrogenase is the only enzyme that catalyzes the reduction of nitrogen gas into ammonia. Nitrogenase is tightly inhibited by the environmental gas carbon monoxide (CO). Many nitrogen fixing bacteria protect nitrogenase from CO inhibition using the protective protein CowN. This work demonstrates that a conserved glutamic acid residue near the C-terminus of Gluconacetobacter diazotrophicus CowN is necessary for its function. Mutation of the glutamic acid residue abolishes both CowN’s protection against CO inhibition and the ability of CowN to bind to nitrogenase. In contrast, a conserved C-terminal cysteine residue is not important for CO protection by CowN. Overall, this work …

Volcanic Diffuse Volatile Emissions Tracked By Plant Responses Detectable From Space, Robert R. Bogue, Peter M. J. Douglas, Joshua B. Fisher, John Stix

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Volcanic volatile emissions provide information about volcanic unrest but are difficult to detect with satellites. Volcanic degassing affects plants by elevating local CO2 and H2O concentrations, which may increase photosynthesis. Satellites can detect plant health, or a reaction to photosynthesis, through a Normalized Difference Vegetation Index (NDVI). This can act as a potential proxy for detecting changes in volcanic volatile emissions from space. We tested this method by analyzing 185 Landsat 5 and 8 images of the Tern Lake thermal area (TLTA) in northeast Yellowstone caldera from 1984 to 2022. We compared the NDVI values of the thermal area with …

Additive Effects Of Cyclic Peptide [R4w4] When Added Alongside Azithromycin And Rifampicin Against Mycobacterium Avium Infection, Melissa Kelley, Kayvan Sasaninia, Arbi Abnousian, Ali Badaoui, James Owens, Abrianna Beever, Nala Kachour, Rakesh Kumar Tiwari, Vishwanath Venketaraman

Pharmacy Faculty Articles and Research

Mycobacterium avium (M. avium), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional treatment consists of a 12-month regimen of the first-line antibiotics rifampicin and azithromycin. However, the treatment duration and low antibiotic tolerability present challenges in the treatment of M. avium infection. Furthermore, the emergence of multidrug-resistant mycobacterium strains prompts a need for novel treatments against M. avium infection. This study aims to test the efficacy of a novel antimicrobial peptide, cyclic [R4W4], alongside the first-line antibiotics azithromycin and rifampicin in reducing M. avium survival. Colony-forming unit (CFU) …

Symbiotic Ucyn-A Strains Co-Occurred With El Niño, Relaxed Upwelling, And Varied Eukaryotes Over 10 Years Off Southern California, Colette Fletcher-Hoppe, Yi-Chun Yeh, Yubin Raut, J. L. Weissman, Jed A. Fuhrman

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Biological nitrogen fixation, the conversion of N₂ gas into a bioavailable form, is vital to sustaining marine primary production. Studies have shifted beyond traditionally studied tropical diazotrophs. Candidatus Atelocyanobacterium thalassa (or UCYN-A) has emerged as a focal point due to its streamlined metabolism, intimate partnership with a haptophyte host, and broad distribution. Here, we explore the environmental parameters that govern UCYN-A’s presence at the San Pedro Ocean Time-series (SPOT), its host specificity, and statistically significant interactions with non-host eukaryotes from 2008-2018. 16S and 18S rRNA gene sequences were amplified by “universal primers” from monthly samples and resolved into Amplicon …

Updating The Dual C And O Isotope—Gas-Exchange Model: A Concept To Understand Plant Responses To The Environment And Its Implications For Tree Rings, Rolf T. W. Siegwolf, Marco M. Lehmann, Gregory R. Goldsmith, Olga V. Churakova (Sidorova), Cathleen Mirande-Ney, Galina Timoveeva, Rosmarie B. Weigt, Matthias Saurer

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The combined study of carbon (C) and oxygen (O) isotopes in plant organic matter has emerged as a powerful tool for understanding plant functional responses to environmental change. The approach relies on established relationships between leaf gas exchange and isotopic fractionation to derive a series of model scenarios that can be used to infer changes in photosynthetic assimilation and stomatal conductance driven by changes in environmental parameters (CO₂, water availability, air humidity, temperature, nutrients). We review the mechanistic basis for a conceptual model, in light of recently published research, and discuss where isotopic observations do not match our …

From Deep Mutational Mapping Of Allosteric Protein Landscapes To Deep Learning Of Allostery And Hidden Allosteric Sites: Zooming In On “Allosteric Intersection” Of Biochemical And Big Data Approaches, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao

Mathematics, Physics, and Computer Science Faculty Articles and Research

The recent advances in artificial intelligence (AI) and machine learning have driven the design of new expert systems and automated workflows that are able to model complex chemical and biological phenomena. In recent years, machine learning approaches have been developed and actively deployed to facilitate computational and experimental studies of protein dynamics and allosteric mechanisms. In this review, we discuss in detail new developments along two major directions of allosteric research through the lens of data-intensive biochemical approaches and AI-based computational methods. Despite considerable progress in applications of AI methods for protein structure and dynamics studies, the intersection between allosteric …

Physiological And Transcriptomic Responses Of Two Artemisia Californica Populations To Drought: Implications For Restoring Drought-Resilient Native Communities, Hagop S. Atamian Dr., Jennifer L. Funk

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

As climate change brings drier and more variable rainfall patterns to many arid and semi-arid regions, land managers must re-assemble appropriate plant communities for these conditions. Transcriptome sequencing can elucidate the molecular mechanisms underlying plant responses to changing environmental conditions, potentially enhancing our ability to screen suitable genotypes and species for restoration. We examined physiological and morphological traits and transcriptome sequences of coastal and inland populations of California sagebrush (Artemisia californica), a critical shrub used to restore coastal sage scrub vegetation communities, grown under low and high rainfall environments. The populations are located approximately 36 km apart but …

Timing And Magnitude Of Drought Impacts On Carbon Uptake Across A Grassland Biome, Andrew Felton, Gregory R. Goldsmith

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Although drought is known to negatively impact grassland functioning, the timing and magnitude of these impacts within a growing season remains unresolved. Previous small-scale assessments indicate grasslands may only respond to drought during narrow periods within a year; however, large-scale assessments are now needed to uncover the general patterns and determinants of this timing. We combined remote sensing datasets of gross primary productivity and weather to assess the timing and magnitude of grassland responses to drought at 5 km² temporal resolution across two expansive ecoregions of the western US Great Plains biome: the C₄-dominated shortgrass steppe and …

Ecological Protection Alone Is Not Enough To Conserve Ecosystem Carbon Storage: Evidence From Guangdong, China, Lihan Cui, Wenwen Tang, Sheng Zheng, Ramesh P. Singh

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The increase in atmospheric CO₂ caused by land use and land cover change (LUCC) is one of the drivers of the global climate. As one of the most typical high-urbanization areas, the ecological conflicts occurring in Guangdong Province warrant urgent attention. A growing body of evidence suggests LUCC could guide the future ecosystem carbon storage, but most LUCC simulations are simply based on model results without full consistency with the actual situation. Fully combined with the territorial spatial planning project and based on the land use pattern in 2010 and 2020, we have used the Markov and Patch-generating Land …

Rapid Bacterial And Fungal Successional Dynamics In First Year After Chaparral Wildfire, M. Fabiola Pulido-Chavez, James W. J. Randolph, Cassandra A. Zalman, Loralee Larios, Peter M. Homyak, Sydney I. Glassman

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The rise in wildfire frequency and severity across the globe has increased interest in secondary succession. However, despite the role of soil microbial communities in controlling biogeochemical cycling and their role in the regeneration of post-fire vegetation, the lack of measurements immediately post-fire and at high temporal resolution has limited understanding of microbial secondary succession. To fill this knowledge gap, we sampled soils at 17, 25, 34, 67, 95, 131, 187, 286, and 376 days after a southern California wildfire in fire-adapted chaparral shrublands. We assessed bacterial and fungal biomass with qPCR of 16S and 18S and richness and composition …

Arginine Methylation Of The Pgc-1Α C‑Terminus Is Temperature- Dependent, Meryl Mendoz, Mariel Mendoza, Tiffany Lubrino, Sidney Briski, Immaculeta Osuji, Janielle Cuala, Brendan Ly, Ivan Ocegueda, Harvey Peralta, Benjamin A. Garcia, Cecilia Zurita-Lopez

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

We set out to determine whether the C-terminus (amino acids 481–798) of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α, UniProt Q9UBK2), a regulatory metabolic protein involved in mitochondrial biogenesis, and respiration, is an arginine methyltransferase substrate. Arginine methylation by protein arginine methyltransferases (PRMTs) alters protein function and thus contributes to various cellular processes. In addition to confirming methylation of the C-terminus by PRMT1 as described in the literature, we have identified methylation by another member of the PRMT family, PRMT7. We performed in vitro methylation reactions using recombinant mammalian PRMT7 and PRMT1 at 37, 30, 21, 18, and 4 °C. …

Technical Note: On Uncertainties In Plant Water Isotopic Composition Following Extraction By Cryogenic Vacuum Distillation, Haoyu Diao, Philipp Schuler, Gregory R. Goldsmith, Rolf T. W. Siegwolf, Matthias Saurer, Marco M. Lehmann

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Recent studies have challenged the interpretation of plant water isotopes obtained through cryogenic vacuum distillation (CVD) based on observations of a large 2H fractionation. These studies have hypothesized the existence of an H-atom exchange between water and organic tissue during CVD extraction with the magnitude of H exchange related to relative water content of the sample; however, clear evidence is lacking. Here, we systematically tested the uncertainties in the isotopic composition of CVD-extracted water by conducting a series of incubation and rehydration experiments using isotopically depleted water, water at natural isotope abundance, woody materials with exchangeable H, and organic materials …

Spatio-Temporal Changes In Vegetation In The Last Two Decades (2001–2020) In The Beijing–Tianjin–Hebei Region, Yuan Zou, Wei Chen, Siliang Li, Tiejun Wang, Le Yu, Min Xu, Ramesh P. Singh, Cong-Qiang Liu

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In terrestrial ecosystems, vegetation is sensitive to climate change and human activities. Its spatial-temporal changes also affect the ecological and social environment. In this paper, we considered the Beijing–Tianjin–Hebei region to study the spatio-temporal vegetation patterns. The detailed analysis of a moderate-resolution imaging spectroradiometer (MODIS) data were carried out through the Google Earth Engine (GEE) platform. Our results show a slow and tortuous upward trend in the average leaf area index (LAI) in the study region for the periods 2001–2020. Specifically, Beijing had the highest LAI value, with an average of 1.64 over twenty years, followed by Hebei (1.30) and …

Open Source Solutions In Experimental Design: An Introduction To The Symposium, Richelle L. Tanner, Kirt L. Onthank

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The Open Science movement has increased dramatically in popularity with deserved calls to action around transparency, access to resources, and inclusion in our field. However, its practical applications within experimental design have been slow to uptake, with researchers unsure where to even start with the dizzying array of open source hardware and software solutions available. The perceived time investment and unknown cost, especially in implementing open source hardware, has stagnated the implementation of inexpensive experimental solutions, but we sought to increase awareness to lower the barrier to participation in this space. While there are countless technical and financial advantages to …

Subtype-Selective Positive Modulation Of KCa2.3 Channels Increases Cilia Length, Young-Woo Nam, Rajasekharreddy Pala, Naglaa Salem El-Sayed, Denisse Laren-Henriquez, Farideh Amirrad, Grace Yang, Mohammad Asikur Rahman, Razan Orfali, Myles Downey, Keykavous Parang, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium (K_Ca2.x) channels are gated exclusively by intracellular Ca²⁺. The activation of K_Ca2.3 channels induces hyperpolarization, which augments Ca²⁺ signaling in endothelial cells. Cilia are specialized Ca²⁺ signaling compartments. Here, we identified compound 4 that potentiates human K_Ca2.3 channels selectively. The subtype selectivity of compound 4 for human K_Ca2.3 over rat K_Ca2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K_Ca2.3 channels by compound 4 increased flow-induced Ca²⁺ signaling and cilia length, while negative …

Prediction Of Cultivation Areas For The Commercial And An Early Flowering Wild Accession Of Salvia Hispanica L. In The United States, Mohammad Hassani, Thomas Piechota, Hagop S. Atamian

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Salvia hispanica L., commonly known as chia, is a plant-based alternative to seafood and is rich in heart-healthy omega-3 fatty acid, protein, fiber, and antioxidants. In the Northern Hemisphere, chia flowering is triggered by the fall equinox (12-h light and dark, early October) and the seeds mature after approximately three months. Chia is sensitive to frost and end of season moisture which limits its cultivation to small areas in regions with temperate climate. The U.S. chia import has increased considerably over the years; however, chia is not widely cultivated in the United States. This study used the historical U.S. temperature …

Virtual Expeditions Facilitated By Open Source Solutions Broaden Student Participation In Natural History Research, Richelle L. Tanner, Talia Y. Moore

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

From its genesis in the Victorian era as an activity for the elite to today's emphasis on “Big Data” and continuous monitoring, natural history has a prominent role in scientific discoveries for many fields. However, participation in field expeditions is limited by funding, space, accessibility, and safety constraints. Others have detailed the active exclusion of minoritized groups from field expeditions and harm/discrimination faced by the few who do participate, but we provide one solution to broaden opportunities for participation in natural history: Virtual Expeditions. Virtual Expeditions are broadly defined as open source, web-facilitated research activities designed to analyze bulk-collected digital …

Climatic Influences On Summer Use Of Winter Precipitation By Trees, Gregory R. Goldsmith, Scott T. Allen, Sabine Braun, Rolf T. W. Siegwolf, James W. Kirchner

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Trees in seasonal climates may use water originating from both winter and summer precipitation. However, the seasonal origins of water used by trees have not been systematically studied. We used stable isotopes of water to compare the seasonal origins of water found in three common tree species across 24 Swiss forest sites sampled in two different years. Water from winter precipitation was observed in trees at most sites, even at the peak of summer, although the relative representation of seasonal sources differed by species. However, the representation of winter precipitation in trees decreased with site mean annual precipitation in both …

Evaluating Alternative Ebullition Models For Predicting Peatland Methane Emission And Its Pathways Via Data–Model Fusion, Shuang Ma, Lifen Jiang, Rachel M. Wilson, Jeff P. Chanton, Scott Bridgham, Shuli Niu, Colleen M. Iversen, Avni Malhotra, Jiang Jiang, Xingjie Lu, Jason Keller, Xiaofeng Xu, Daniel M. Ricciuto, Paul J. Hanson, Yiqi Luo

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Understanding the dynamics of peatland methane (CH₄) emissions and quantifying sources of uncertainty in estimating peatland CH₄ emissions are critical for mitigating climate change. The relative contributions of CH₄ emission pathways through ebullition, plant-mediated transport, and diffusion, together with their different transport rates and vulnerability to oxidation, determine the quantity of CH₄ to be oxidized before leaving the soil. Notwithstanding their importance, the relative contributions of the emission pathways are highly uncertain. In particular, the ebullition process is more uncertain and can lead to large uncertainties in modeled CH₄ emissions. To improve model simulations …

Evaluating Alternative Ebullition Models For Predicting Peatland Methane Emission And Its Pathways Via Data–Model Fusion, Shuang Ma, Lifen Jiang, Rachel M. Wilson, Jeff P. Chanton, Scott Bridgham, Shuli Niu, Colleen M. Iversen, Avni Malhotra, Jiang Jiang, Xingjie Lu, Yuanyuan Huang, Jason Keller, Xiaofeng Xu, Daniel M. Ricciuto, Paul J. Hanson, Yiqi Luo

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Understanding the dynamics of peatland methane (CH4) emissions and quantifying sources of uncertainty in estimating peatland CH4 emissions are critical for mitigating climate change. The relative contributions of CH4 emission pathways through ebullition, plant-mediated transport, and diffusion, together with their different transport rates and vulnerability to oxidation, determine the quantity of CH4 to be oxidized before leaving the soil. Notwithstanding their importance, the relative contributions of the emission pathways are highly uncertain. In particular, the ebullition process is more uncertain and can lead to large uncertainties in modeled CH4 emissions. To improve model simulations of CH4 emission and its pathways, …

1st Place Contest Entry: Designing Hollow Nanogels For Drug Delivery Applications, Mo Hijazi

Kevin and Tam Ross Undergraduate Research Prize

This is Mo Hijazi's submission for the 2022 Kevin and Tam Ross Undergraduate Research Prize, which won first place. It contains their essay on using library resources, their bibliography, and a summary of their research project on hollow-core nanogels.

Mo is a second-year student at Chapman University, majoring in Biological Sciences. Their faculty mentor is Dr. Molla Islam.

A Push For Inclusive Data Collection In Stem Organizations, Nicholas P. Burnett, Alyssa M. Hernandez, Emily E. King, Richelle L. Tanner, Kathryn Wilsterman

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Professional organizations in STEM (science, technology, engineering, and mathematics) can use demographic data to quantify recruitment and retention (R&R) of underrepresented groups within their memberships. However, variation in the types of demographic data collected can influence the targeting and perceived impacts of R&R efforts - e.g., giving false signals of R&R for some groups. We obtained demographic surveys from 73 U.S.-affiliated STEM organizations, collectively representing 712,000 members and conference-attendees. We found large differences in the demographic categories surveyed (e.g., disability status, sexual orientation) and the available response options. These discrepancies indicate a lack of consensus regarding the demographic groups that …

Dissecting Mutational Allosteric Effects In Alkaline Phosphatases Associated With Different Hypophosphatasia Phenotypes: An Integrative Computational Investigation, Fei Xiao, Ziyun Zhou, Xingyu Song, Mi Gan, Jie Long, Gennady M. Verkhivker, Guang Hu

Mathematics, Physics, and Computer Science Faculty Articles and Research

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of ALPL mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the ALPL mutations on protein dynamics and function. Statistical analysis of molecular features computed for the …

Structural And Computational Studies Of The Sars-Cov-2 Spike Protein Binding Mechanisms With Nanobodies: From Structure And Dynamics To Avidity-Driven Nanobody Engineering, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural …

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …