The oxidation of the [4Fe-4S] Cluster of DNA Primase Alters the Binding Interactions with DNA and RNA Primers Thursday, May 9, 2024 DNA primase is an iron sulfur enzyme in DNA replication, responsible for synthesizing short RNA primers that serve as starting points for DNA synthesis. The role of the [4Fe-4S] cluster is not well determined. Here, we calculate the redox potential (Em) of the [4Fe-4S] with and without DNA/RNA using continuum electrostatics. In addition, we identify the structural changes coupled to the oxidation/reduction. Our calculations show that the DNA/RNA primer lowers the Em by 110 mV and 50 mV for the [4Fe-4S]+ and [4Fe-4S]2+ states respectively. Read more
DyMMM-LEAPS: An ML-based framework for modulating evenness and stability in synthetic microbial communities Thursday, May 9, 2024 There have been a growing number of computational strategies to aid in the design of synthetic microbial consortia. A framework to identify regions in parametric space to maximize two essential properties, evenness and stability, is critical. In this study, we introduce DyMMM-LEAPS (Dynamic Multi-species Metabolic Modeling - Locating Evenness And stability in large Parametric Space), an extension of the DyMMM framework. Our method explores the large parametric space of genetic circuits in synthetic microbial communities to identify regions of evenness and stability. Read more
Modeling Allosteric Mechanisms of Eukaryotic Type II Topoisomerases Wednesday, May 8, 2024 Type II topoisomerases (TopoIIs) are ubiquitous enzymes that are involved in crucial nuclear processes such as genome organization, chromosome segregation, and other DNA metabolic processes. These enzymes function as large, homodimeric complexes that undergo a complex cycle of binding and hydrolysis of two ATP molecules in their ATPase domains, which regulates the capture and passage of one DNA double-helix through a second, cleaved DNA molecule. This process requires the transmission of information about the state of the bound nucleotide over vast ranges in the TopoII complex. Read more
Spatial heterogeneity in tumor adhesion qualifies collective cell invasion. Wednesday, May 8, 2024 Collective cell invasion (CCI), a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. Read more
Quantifying cell cycle regulation by tissue crowding Monday, May 6, 2024 SIGNIFICANCE The correct regulation of cell proliferation is crucial for the emergence of collective cell behaviour during tissue morphogenesis, homeostasis and regeneration. Moreover, uncontrolled cell division often leads to tumour formation. Here, we propose a mathematical model of cell migration with cell cycle dynamics which accounts for density-dependent effects regulating cell cycle progression. Our model is capable of describing the spatiotemporal cell cycle dynamics observed during epithelial tissue expansion. By combining experimental data, Bayesian inference, and minimal modelling, we describe how each cell cycle phase depends on local cell density, and quantify the impact of tissue crowding on cell proliferation patterns. Read more
Spectral neural approximations for models of transcriptional dynamics Monday, May 6, 2024 The advent of high-throughput transcriptomics provides an opportunity to advance mechanistic understanding of transcriptional processes and their connections to cellular function at an unprecedented, genome-wide scale. These transcriptional systems, which involve discrete, stochastic events, are naturally modeled using Chemical Master Equations (CMEs), which can be solved for probability distributions to fit biophysical rates that govern system dynamics. While CME models have been used as standards in fluorescence transcriptomics for decades to analyze single species RNA distributions, there are often no closed-form solutions to CMEs that model multiple species, such as nascent and mature RNA transcript counts. Read more
Reconstruction of the real 3D shape of the SARS-CoV-2 virus Monday, May 6, 2024 The photographs of the SARS-CoV-2 virus taken by electron transmission microscopy and Cryo-electron microscopy provide only a 2D silhouette. The viruses appear to look like distorted circles. The present paper questions the real shape of the SARS-CoV-2 virus and makes an attempt to give an answer. Is this a general ellipsoid, a spheroid with rotational symmetry, a sphere, or something else? The answer requires the application of tools from three different disciplines, structural mechanics, microbiology, and statistics. Read more
A role for conformational changes in enzyme catalysis Friday, May 3, 2024 The role played by conformational changes in enzyme catalysis is controversial. In addition to examining specific enzymes, studying formal models can help identify the conditions under which conformational changes promote catalysis. Here, we present a model demonstrating how conformational changes can break a generic trade-off due to the conflicting requirements of successive steps in catalytic cycles, namely high specificity for the transition state to accelerate the chemical transformation and low affinity for the products to favor their release. Read more
OrganL: Dynamic Triangulation of Biomembranes using Curved Elements Friday, May 3, 2024 Our method provides a straightforward way to simulate any biomembrane geometry. It overcomes some of the limitations of previous dynamically triangulated surface (DTS) Monte Carlo schemes by providing a surface that contains an interpolant which allows to assign meaningful functions of curvature to almost every point of the discretization, yet keeps much of the simplicity of the common DTS schemes by not requiring any nonlocal information or iterations for its construction. Our tool is easily extensible and facilitates the simulation of complex lipid and protein compositions on membrane surfaces at any scale. Read more
Parkinson’s Disease-associated mutations in α-synuclein alters its lipid-bound state Thursday, May 2, 2024 Lipid binding properties of α-synuclein play a central role in protein aggregation and progression of Parkinson’s Disease (PD). α-Synuclein, an intrinsically disordered protein, binds to lipid membranes through the formation of two amphipathic helices that insert into the lipid bilayer. All disease-associated single point mutations have been identified to be within these helical regions of α-synuclein: V15A, A30P, E46K, H50Q, G51D, A53T, and A53V. However, the effects of these mutations on the bound states of the two α-helices of the protein have yet to be fully characterized. Read more
Fluorescence lifetime imaging microscopy of flexible and rigid dyes probes the biophysical properties of synthetic and biological membranes Thursday, May 2, 2024 Sensing of the biophysical properties of membranes using molecular reporters has recently regained wide-spread attention. This was elicited by the development of new probes of exquisite optical properties and increased performance, combined with developments in fluorescence detection. Here, we report on fluorescence lifetime imaging (FLIM) of various rigid and flexible fluorescent dyes to probe the biophysical properties of synthetic and biological membranes at steady state as well as upon the action of external membrane-modifying agents. Read more
Simulations predict preferred Mg2+ coordination in a nonenzymatic primer extension reaction center Wednesday, May 1, 2024 The mechanism by which genetic information was copied prior to the evolution of ribozymes is of great interest because of its importance to the origin of life. The most effective known process for the nonenzymatic copying of an RNA template is primer extension by a two-step pathway in which 2-aminoimidazole activated nucleotides first react with each other to form an imidazolium-bridged intermediate that subsequently reacts with the primer. Reaction kinetics, structure-activity relationships, and X-ray crystallography have provided insight into the overall reaction mechanism, but many puzzles remain. Read more